Cycloalkane[B]indole antagonists of prostaglandin D2 receptors

ABSTRACT

Described herein are compounds that are antagonists of PGD 2  receptors. Also described are pharmaceutical compositions and medicaments that include the compounds described herein that are antagonists of PGD 2  receptors. Also described herein are methods of using such antagonists of PGD 2  receptors, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other PGD 2 -dependent or PGD 2 -mediated conditions or diseases.

RELATED APPLICATIONS

This application is filed pursuant to 35 U.S.C. §371 as a United StatesNational Phase Application of International Application No.PCT/US2009/048327, entitled “CYCLOALKANE[B]INDOLE ANTAGONISTS OFPROSTAGLANDIN D₂ RECEPTORS” filed Jun. 23, 2009, which claims thebenefit of U.S. provisional patent application No. 61/075,242 entitled“CYCLOALKANE[B]INDOLE ANTAGONISTS OF PROSTAGLANDIN D₂ RECEPTORS” filedon Jun. 24, 2008, all of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments comprising such compounds,and methods of using such compounds to treat, prevent or diagnosediseases, disorders or conditions associated with prostaglandin D₂.

BACKGROUND OF THE INVENTION

Prostaglandins are acidic lipids derived from the metabolism ofarachidonic acid by the action of cyclooxygenase enzymes and downstreamsynthases. Prostaglandins have a diverse range of activities and have awell recognized role in pain and inflammation. Prostaglandin D₂ (PGD₂)is an acidic lipid mediator derived from the metabolism of arachidonicacid by cyclooxygenases and PGD₂ synthases. PGD₂ is produced by mastcells, macrophages and Th2 lymphocytes in response to local tissuedamage as well as allergic inflammation in diseases such as asthma,rhinitis, and atopic dermatitis. Exogenous PGD₂ applied to bronchialairways elucidates many characteristics of an asthmatic responsesuggesting that PGD₂ plays an important pro-inflammatory role inallergic diseases.

PGD₂ binds to a number of receptors, which include the thromboxane-typeprostanoid (TP) receptor, PGD₂ receptor (DP, also known as DP₁) andchemoattractant receptor-homologous molecule expressed on Th2 cells(CRTH2; also known as DP₂). DP₂ is associated with promoting chemotaxisand activation of Th2 lymphocytes, eosinophils and basophils. Inparticular, PGD₂ binds to DP₂, and mediates its effects through aG₁-dependant elevation in calcium levels and reduction of intracellularcyclic AMP. In Th2 lymphocytes, IL4, IL5 and IL13 cytokine production isstimulated. These cytokines have been implicated in numerous biologicalactions including, by way of example only, immunoglobulin E production,airway response, mucous secretion, and eosinophil recruitment.

SUMMARY OF THE INVENTION

Presented herein are compounds, pharmaceutical compositions andmedicaments, methods, for (a) diagnosing, preventing, or treatingallergic and non-allergic inflammation, (b) mitigating adverse signs andsymptoms that are associated with inflammation, and/or (c) controllingimmunological, proliferative or metabolic disorders. These disorders mayarise from one or more of a genetic, iatrogenic, immunological,infectious, metabolic, oncological, toxic, surgical, and/or traumaticetiology. In one aspect, the methods, compounds, pharmaceuticalcompositions, and medicaments described herein comprise antagonists ofPGD₂ receptors. In one aspect, the methods, compounds, pharmaceuticalcompositions, and medicaments described herein comprise antagonists ofDP₂.

In some embodiments provided herein are compounds of Formula (I),pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs,and pharmaceutically acceptable solvates thereof, which are antagonistsof DP₂, and are used to treat subjects suffering from one or morePGD₂-dependent conditions or diseases, including, but not limited to,asthma, rhinitis, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis,inflammatory bowel disease, adult respiratory distress syndrome,myocardial infarction, aneurysm, stroke, cancer, endotoxic shock,proliferative disorders and inflammatory conditions. In someembodiments, PGD₂-dependent conditions or diseases include those whereinan absolute or relative excess of PGD₂ is present and/or observed.

In some embodiments provided herein is a compound having the structureof Formula (I), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof:

-   -   wherein,    -   R¹, R², R³, and R⁴ each are independently selected from H,        halogen, —CN, —NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹²,        —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³,        —OCO₂R¹², —N(R¹³)₂, —C(═O)N(R¹³)₂, —OC(═O)N(R¹³)₂, —NHC(═O)R¹²,        —NHC(═O)OR¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,        C₁-C₆alkoxy, C₁-C₆heteroalkyl, an optionally substituted        cycloalkyl, an optionally substituted heterocycloalkyl,        optionally substituted phenyl, and an optionally substituted        monocyclic heteroaryl;    -   R⁵ is L⁵-X⁵;        -   L⁵ is —C₁-C₆alkyl-, —C₁-C₆flouroalkyl-, or            —C₃-C₆cycloalkyl-, —C₁-C₆alkyl- (an optionally substituted            aryl)-, —C₁-C₆alkyl- (an optionally substituted            heteroaryl)-, an optionally substituted aryl, or an            optionally substituted heteroaryl;        -   X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂,            —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹²,            —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹²,            —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂,            —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or            —C(═NR¹⁴)N(R¹³)₂;    -   R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocycloalkyl, an optionally substituted aryl, an optionally        substituted heteroaryl, —C₁-C₆alkyl- (an optionally substituted        cycloalkyl), —C₁-C₆alkyl- (an optionally substituted        heterocycloalkyl), —C₁-C₆alkyl- (an optionally substituted        aryl), or —C₁-C₆alkyl- (an optionally substituted heteroaryl);    -   R⁷ is L⁷-X⁷;        -   L⁷ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, or an optionally            substituted C₃-C₆cycloalkyl;        -   X⁷ is —CO₂H, —CO₂R¹², —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂,            —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹²,            —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹²,            —OH, —OR¹², —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂,            —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or            —C(═NR¹⁴)N(R¹³)₂;    -   each R⁸ and R⁹ is independently selected from H, C₁-C₄alkyl, and        C₁-C₄haloalkyl; or    -   two R⁸ groups are taken together with the carbon atom to which        they are attached to form a carbonyl (—C(═O)—); or    -   both R⁹ groups are taken together with the carbon atom to which        they are attached to form a carbonyl (—C(═O)—);    -   R¹⁰ is H, C₁-C₄alkyl, C₁-C₄haloalkyl, or -L¹⁰-X¹⁰;        -   L¹⁰- is —C₁-C₆alkyl-, —C₃-C₆cycloalkyl-, —C₁-C₆alkyl- (an            optionally substituted aryl)- or —C₁-C₆alkyl- (an optionally            substituted heteroaryl)-;        -   X¹⁰ is —CO₂R¹³, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH,            —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂,            —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OR¹³, —SR¹²,            —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹²,            —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)_(N)(R¹³)₂;    -   R¹² is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, optionally        substituted benzyl or optionally substituted heteroaryl;    -   each R¹³ is independently selected from H, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, an optionally substituted        cycloalkyl, an optionally substituted heterocycloalkyl, an        optionally substituted aryl, an optionally substituted benzyl,        and an optionally substituted heteroaryl;    -   two R¹³ groups attached to the same N atom are taken together        with the N atom to which they are attached to form an optionally        substituted heterocycloalkyl;    -   R¹⁴ is selected from among H, —S(═O)₂R¹², —S(═O)₂NH₂, —C(═O)R¹²,        —CN, and —NO₂;    -   m is 1, 2, or 3.

For any and all of the embodiments, substituents can be selected fromamong from a subset of the listed alternatives. For example, in someembodiments, m is 1 or 2. In some embodiments, m is 1. In someembodiments, m is 2.

In some embodiments, X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹²,—C(═O)N(R¹³)₂, —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹²,—S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹³,—SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹²,—SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂. In someembodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂,—C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂,—NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹³, —SR¹², —S(═O)R¹²,—S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹²,—SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂. In some embodiments, X⁵ is—CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂,—NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —SR¹², —S(═O)R¹², —S(═O)₂R¹², or—N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂,—NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, or—N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂,—S(═O)₂N(R¹³)₂, or —OH. In some embodiments, X⁵ is —CO₂R¹³,—C(═O)N(R¹³)₂, or —OH.

In some embodiments, each R⁸ and R⁹ is each independently selected fromH, or —CH₃; or two R⁸ groups are taken together with the carbon atom towhich they are attached to form a carbonyl(-C(═O)—); or both R⁹ groupsare taken together with the carbon atom to which they are attached toform a carbonyl(-C(═O)—); and m is 1 or 2. In some embodiments, each R⁸and R⁹ is H.

In some embodiments, R¹, R², R³, and R⁴ each are independently selectedfrom H, halogen, —CN, —NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹²,—S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³,—OCO₂R¹², —N(R¹³)₂, —C(═O)N(R¹³)₂, —OC(═O)N(R¹³)₂, —NHC(═O)R¹²,—NHC(═O)OR¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, C₁-C₆heteroalkyl, an optionally substituted cycloalkyl, anoptionally substituted heterocycloalkyl, optionally substituted phenyl,and an optionally substituted monocyclic heteroaryl, provided that atleast two of R¹, R², R³, and R⁴ are H.

In some embodiments, R¹, R², R³, and R⁴ each are independently selectedfrom H, halogen, —CN, —OH, —OR¹³, —S(═O)₂C₁-C₆alkyl, —S(═O)₂N(R¹³)₂,—NHS(═O)₂R¹², —OC(═O)R¹², —C(═O)N(R¹³)₂, —NHC(═O)R¹², C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.In some embodiments, R¹, R², R³, and R⁴ each are independently selectedfrom H, halogen, —CN, —OH, —OR¹³, —S(═O)₂C₁-C₆alkyl, —S(═O)₂N(R¹³)₂,—NHS(═O)₂R¹², —OC(═O)R¹², —C(═O)N(R¹³)₂, —NHC(═O)R¹², C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl,provided that at least two of R¹, R², R³, and R⁴ are H.

In some embodiments, R¹, R², R³, and R⁴ each are independently selectedfrom H, halogen, —CN, —OH, —S(═O)₂C₁-C₆alkyl, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, C₁-C₄alkoxy, and C₁-C₄heteroalkyl.

In some embodiments, at least two of R¹, R², R³, and R⁴ is H. In someembodiments, at least three of R¹, R², R³, and R⁴ is H. In someembodiments, each of R¹, R², R³, and R⁴ is H.

In some embodiments, R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, an optionally substituted C₃-C₁₀cycloalkyl, anoptionally substituted phenyl, an optionally substituted naphthyl, anoptionally substituted monocyclic heteroaryl containing 0-3 N atoms, anoptionally substituted —C₁-C₆alkyl-cycloalkyl, an optionally substituted—C₁-C₆alkyl-phenyl, or an optionally substituted —C₁-C₆alkyl-(monocyclicheteroaryl).

In some embodiments, R⁶ is an optionally substituted phenyl, anoptionally substituted naphthyl, an optionally substituted monocyclicheteroaryl containing 0-3 N atoms.

In some embodiments, R⁶ is an optionally substituted C₃-C₁₀cycloalkyl,an optionally substituted C₂-C₁₀heterocycloalkyl, an optionallysubstituted phenyl, an optionally substituted napthyl, an optionallysubstituted monocyclic heteroaryl containing 0-3 N atoms.

In some embodiments, L⁷ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, or anoptionally substituted C₃-C₆cycloalkyl; X⁷ is —CO₂R¹³, —C(═O)N(R¹³)₂,tetrazolyl, —OH, or —C(═O)NHC(═O)R¹². In some embodiments, L⁷ isC₁-C₆alkyl. In some embodiments, L⁷ is C₁-C₄alkyl.

In some embodiments, L⁵ is —C₁-C₆alkyl, or —C₁-C₆alkyl- (an optionallysubstituted phenyl); and X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹²,—C(═O)N(R¹³)₂, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹²,—NHC(═O)R¹², —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², or —N(R¹³)₂. Insome embodiments, L⁵ is —C₁-C₆alkyl.

In some embodiments, L⁵ is C₁-C₆alkyl; X⁵ is F, —CO₂R¹³, —CN,—C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂,—NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —OR¹³, —SR¹², —S(═O)₂R¹², or —N(R¹³)₂.In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —NHS(═O)₂R¹²,—S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —S(═O)₂R¹², or—N(R¹³)₂.

In some embodiments, L⁷ is C₁-C₆alkyl; X⁷ is CO₂H, —CO₂(C₁-C₆alkyl), or—OH. In some embodiments, X⁷ is CO₂H, or —OH.

In some embodiments, R¹⁰ is H or C₁-C₄alkyl.

In some embodiments, each of R⁸ and R⁹ is H.

In some embodiments, the compound of Formula (I) has the followingstructure:

In some embodiments, m is 1.

In some embodiments, the compound of Formula (I) has the structure ofFormula (II):

In some embodiments, m is 2.

In some embodiments, the compound of Formula (I) has the structure ofFormula (II):

In some embodiments, R¹⁰ is H or —CH₃. In some embodiments, R¹⁰ is H. Insome embodiments, R¹⁰ is —CH₃.

In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —OH, or —OR¹³.In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, or —OH. In someembodiments, X⁵ is —CO₂R¹³, —C(═O)N(R¹³)₂, or —OH.

In some embodiments, R¹, R², R³, and R⁴ each are independently selectedfrom H, F, Cl, Br, I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and —CF₃; andR¹⁰ is H. In some embodiments, R¹, R², R³, and R⁴ are independentlyselected from H, F, Cl, Br, I, —CN, −OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and—CF₃, provided that at least two of R¹, R², R³, and R⁴ are H. In oneaspect, each of R¹, R², R³, and R⁴ are H.

In some embodiments, R⁷ is —CH₂CO₂H, —CH₂CH₂CO₂H, —C(CH₃)₂OH,—CH₂C(CH₃)₂OH, or —CH₂CH₂C(CH₃)₂OH.

In some embodiments, R⁵ is —CH₂CH₂OH, —CH₂CO₂H, —CH₂CH(CH₃)OH,—CH₂C(CH₃)₂OH, —CH₂CH₂OH, —(CH₂)₂CO₂H, —CH₂-tetrazolyl, —CH₂C(═O)NH₂, or—(CH₂)₂C(═O)NH₂.

In some embodiments, R⁵ is —CH₂CO₂H, —CH₂C(CH₃)₂OH, or —CH₂C(═O)NH₂.

In some embodiments, R⁶ is an optionally substituted phenyl. In someembodiments, R⁶ is an optionally substituted phenyl, where if the phenylis susbtituted then the phenyl is substituted with one or two groupsselected from F, Cl, Br, I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and —CF₃.In some embodiments, R⁶ is an optionally substituted phenyl, where ifthe phenyl is susbtituted then the phenyl is substituted with F, Cl, Br,I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, or —CF₃. In some embodiments, R⁶is 4-fluorophenyl.

Any combination of the groups described above for the various variablesis contemplated herein.

In some embodiments, the compound of Formula (I) is selected from among:{3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-aceticacid (Compound 1-1);{(4-Fluoro-benzenesulfonyl)-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino}-aceticacid (Compound 1-2);3-{3-[(4-Fluoro-benzenesulfonyl)-(2-hydroxy-2-methyl-propyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionicacid (Compound 1-3);4-FluoroN-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-(2-hydroxy-2-methyl-propyl)-benzenesulfonamide(Compound 1-4);3-{3-[Carbamoylmethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionicacid (Compound 1-5); and3-{3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionicacid (Compound 1-6).

Also provided herein is a pharmaceutical composition comprising atherapeutically effective amount of a compound of any of Formulas (I),(II), or (III), or a pharmaceutically acceptable salt thereof, and atleast one pharmaceutically acceptable inactive ingredient selected frompharmaceutically acceptable diluents, pharmaceutically acceptableexcipients, and pharmaceutically acceptable carriers. In someembodiments, the pharmaceutical composition is formulated forintravenous injection, oral administration, inhalation, buccaladministration, transdermal administration, nasal administration,topical administration, ophthalmic administration or oticadministration. In some embodiments, the pharmaceutical composition is atablet, a pill, a capsule, a liquid, an inhalant, a nasal spraysolution, a suppository, a suspension, a gel, a colloid, a dispersion, asuspension, a solution, an emulsion, an ointment, a lotion, an eye dropor an ear drop. In some embodiments, the composition further comprisesone or more additional therapeutically active agents selected from5-lipoxygenase-activating protein inhibitors, 5-lipoxygenase inhibitors,CYSLTR1 antagonists, CYSLTR2 antagonists, BLT1 antagonists, BLT2antagonists, thromboxane antagonists, DP1 receptor antagonists, DP1receptor agonists, IP receptor agonists, anti-IgE, chemokine receptorantagonists, IL5 antibody, bronchodilators, theophylline, leukotrienereceptor antagonists, leukotriene formation inhibitors, decongestants,antihistamines, mucolytics, corticosteroids, glucocorticoids,anticholinergics, antitussives, analgesics, expectorants, and β-2agonists. In some embodiments, the effective amount is an amountsufficient to ameliorate the symptoms of a PGD₂-dependent orPGD₂-mediated disease or condition in a subject in need thereof. In someembodiments, the subject is a human.

Also provided herein is a medicament for treating a PGD₂-dependent orPGD₂-mediated disease or condition in a subject comprising atherapeutically effective amount of a compound of any of Formulas (I),(II), or (III). In some embodiments, the subject is a human.

Also provided herein is the use of a compound of any of Formulas (I),(II), or (III) in the manufacture of a medicament for the treatment of aPGD₂-dependent or PGD₂-mediated disease or condition.

Also provided herein is a method for treating PGD₂-dependent orPGD₂-mediated disease or condition in a subject comprising administeringto the subject a therapeutically effective amount of a compound of anyof Formulas (I), (II), or (III). In some embodiments, the PGD₂-dependentor PGD₂-mediated disease or condition is selected from asthma, rhinitis,allergic conjuctivitis, atopic dermatitis, chronic obstructive pulmonarydisease (COPD), pulmonary hypertension, interstitial lung fibrosis,cystic fibrosis, arthritis, allergy, psoriasis, inflammatory boweldisease, adult respiratory distress syndrome, myocardial infarction,aneurysm, stroke, cancer, wound healing, endotoxic shock, pain,inflammatory conditions, eosinophilic esophagitis, eosinophil-associatedgastrointestinal disorders (EGID), idiopathic hypereosinophilicsyndrome, otitis, airway constriction, mucus secretion, nasalcongestion, increased microvascular permeability and recruitment ofeosinophils, urticaria, sinusitis, angioedema, anaphylaxia, chroniccough and Churg Strauss syndrome. In some embodiments, thePGD₂-dependent or PGD₂-mediated disease or condition is a respiratorydisorder. In some embodiments, the respiratory disorder is asthma,rhinitis or chronic obstructive pulmonary disease (COPD). In someembodiments, the method further comprises administering to the subject asecond therapeutic agent selected from 5-lipoxygenase-activating proteininhibitors, 5-lipoxygenase inhibitors, CYSLTR1 antagonists, CYSLTR2antagonists, BLT1 antagonists, BLT2 antagonists, thromboxaneantagonists, DP1 receptor antagonists, DP1 receptor agonists, IPreceptor agonists, anti-IgE, chemokine receptor antagonists, ILSantibody, bronchodilators, theophylline, leukotriene receptorantagonists, leukotriene formation inhibitors, decongestants,antihistamines, mucolytics, corticosteroids, glucocorticoids,anticholinergics, antitussives, analgesics, expectorants, and β-2agonists. In some embodiments, the subject is a human.

In some embodiments, compounds having the structure of Formula (I),(II), or (III) are used in treating a disease or condition mediated byprostaglandin D₂. In some embodiments, the disease or condition is arespiratory disease or condition, an allergic disease or condition, oran inflammatory disease or condition. In some embodiments, the diseaseor condition is a respiratory disease or condition or an allergicdisease or condition. In some embodiments, the disease or condition isasthma, rhinitis or chronic obstructive pulmonary disease (COPD). Insome embodiments, the disease or condition is asthma. In someembodiments, the disease or condition is rhinitis. In some embodiments,the disease or condition is chronic obstructive pulmonary disease(COPD).

In another aspect, compounds of Formula (I), (II), or (III) are used totreat or prevent immunological disorders, including, but are not limitedto, allergy or to excessive or inappropriate response to an endogenousor exogenous antigen. In certain embodiments, the immunological disorderthat is characterized by immune dysregulation that is not accompanied byinflammation.

In additional aspects, such diseases or conditions are iatrogenic andincreases in, or abnormal localization of, PGD₂ is induced by othertherapies or medical or surgical procedures. In other embodiments, thePGD₂-dependent or PGD₂ mediated condition or disease is caused bysurgery.

In another aspect are methods for treating respiratory diseases orconditions in a mammal comprising administering to the mammal at leastonce an effective amount of at least one compound of Formula (I), (II),or (III). In a further embodiment of this aspect, the respiratorydisease is asthma. In a further embodiment of this aspect, therespiratory disease includes, but is not limited to, asthma, adultrespiratory distress syndrome, allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitiveasthma, exercise-induced asthma, neutrophillic asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, seasonal asthma,seasonal allergic rhinitis, perennial allergic rhinitis, chronicobstructive pulmonary disease, including chronic bronchitis oremphysema, pulmonary hypertension, interstitial lung fibrosis and/orairway inflammation and cystic fibrosis, and hypoxia.

In another aspect compounds described herein are used for treatingrhinitis in a mammal. In a further embodiment of this aspect, compoundsdescribed herein are used for treating allergic (extrinsic) rhinitis,non-allergic (intrinsic) rhinitis, chronic rhinitis, allergen-inducedrhinitis, aspirin-sensitive rhinitis, child-onset rhinitis, adult-onsetrhinitis, occupational rhinitis, steroid-resistant rhinitis, seasonalrhinitis, perennial rhinitis, rhinosinusitis, and rhinopolyposis.

In another aspect are methods for treating chronic obstructive pulmonarydisease comprising administering to the mammal at least once aneffective amount of a compound of Formula (I), (II), or (III). In afurther embodiment of this aspect, chronic obstructive pulmonary diseaseincludes, but is not limited to, chronic bronchitis and/or emphysema,pulmonary hypertension, interstitial lung fibrosis and/or airwayinflammation and cystic fibrosis.

In another aspect are methods for preventing increased mucosal secretionand/or edema in mammals comprising administering to the mammal at leastonce an effective amount of a compound of Formula (I), (II), or (III).

In another aspect are methods for preventing eosinophil and/or basophiland/or dendritic cell and/or neutrophil and/or monocyte or Th2 cellrecruitment comprising administering to the mammal an effective amountof a compound of Formula (I), (II), or (III).

In another aspect are methods for treating or preventing ocularinflammation, conjunctivitis, retinitis, scleritis, uveitis, allergicconjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis comprising administering to the mammal at least once aneffective amount of a compound of Formula (I), (II), or (III).

In another aspect, compounds of Formula (I), (II), or (III) are used totreat or prevent pain.

In another aspect are methods for preventing or treating acute orchronic disorders involving recruitment or activation of eosinophilscomprising administering to the mammal at least once an effective amountof a compound of Formula (I), (II), or (III).

In another aspect are methods for treating inflammatory responses of theskin comprising administering to the mammal at least once an effectiveamount of at least one compound of Formula (I), (II), or (III). Suchinflammatory responses of the skin include, by way of example,psoriasis, dermatitis, atopic dermatitis, contact dermatitis, eczema,urticaria, rosacea, bullous disorders, collagenoses, Kawasaki Disease,Sjogren-Larsso Syndrome, wound healing and scarring. In another aspectare methods for reducing psoriatic lesions in the skin, joints, or othertissues or organs, comprising administering to the mammal an effectiveamount of a compound of Formula (I), (II), or (III). In another aspectare methods for reducing psoriatic lesions in the skin, joints, or othertissues or organs, comprising administering at least once to the mammalan effective amount of a compound of Formula (I), (II), or (III).

In a further aspect are methods to modulate the immune response toendogenous or exogenous antigens. In a further aspect are methods totreat acute or chronic allergic responses to exogenous substances thathave been ingested such as foods (e.g., peanuts) or drugs (e.g.,penicillin, non-steroidal anti-inflammatory drugs or the like).

In another aspect is the use of a compound of Formula (I), (II), or(III) in the manufacture of a medicament for treating an inflammatorydisease or condition in a mammal in which the activity of at least onePGD₂-associated protein contributes to the pathology and/or symptoms ofthe disease or condition. In one embodiment of this aspect, the PGD₂pathway protein is DP2. In another or further embodiment of this aspect,the inflammatory disease or conditions are respiratory, cardiovascular,or proliferative diseases.

In any of the aforementioned aspects are further embodiments in which:(a) the effective amount of the compound is systemically administered tothe mammal; and/or (b) the effective amount of the compound isadministered orally to the mammal; and/or (c) the effective amount ofthe compound is intravenously administered to the mammal; and/or (d) theeffective amount of the compound administered by inhalation; and/or (e)the effective amount of the compound is administered by nasaladministration; or and/or (f) the effective amount of the compound isadministered by injection to the mammal; and/or (g) the effective amountof the compound is administered topically (dermal) to the mammal; and/or(h) the effective amount of the compound is administered by ophthalmicadministration; and/or (i) the effective amount of the compound isadministered rectally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce daily; (ii) the compound is administered twice daily; (iii) thecompound is administered in cycles that include daily administration fora period of time followed by at least 1 day without administration; (iv)the compound is administered in cycles that include daily administrationfor a period of time followed by at least 1 day that includes a dosereduction in the daily amount of compound that is administered.

In any of the aforementioned aspects involving the treatment of PGD₂dependent diseases or conditions are further embodiments comprisingadministering at least one additional agent in addition to theadministartion of a compound having the structure of Formula (I).

In any of the aforementioned aspects involving the prevention ortreatment of inflammation are further embodiments comprising: (a)monitoring inflammation in a mammal; (b) measuring bronchoconstrictionin a mammal; (c) measuring eosinophil and/or basophil and/or dendriticcell and/or neutrophil and/or monocyte and/or lymphocyte recruitment ina mammal; (d) monitoring mucosal secretion in a mammal; (e) measuringmucosal edema in a mammal.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Prostaglandin D₂ (PGD₂) is an acidic lipid derived from the metabolismof arachidonic acid by cyclooxygenases and PGD₂ synthases. PGD₂ isproduced by mast cells, macrophages and Th2 lymphocytes in response tolocal tissue damage as well as in response allergic inflammationobserved in diseases such as asthma, rhinitis, and atopic dermatitis.More specifically, exogenous PGD₂ applied to bronchial airways elicitsmany responses that are characteristic of acute asthma.

PGD₂ is a major mast cell product that acts via two receptors, theD-type prostanoid (DP, also known as DP₁) and the chemoattractantreceptor-homologous molecule expressed on Th2 cells (CRTH2, also knownas DP₂) receptors. DP₂ mediates the chemotaxis of eosinophils,basophils, and Th2 lymphocytes, and DP₁ receptor plays an important rolein eosinophil trafficking. DP₁ antagonists do not inhibit the release ofeosinophils when induced by the DP₂-selective agonists. However,eosinophils in human bone marrow specimens express DP₁ and DP₂ receptorsat similar levels and human peripheral blood expresses both DP₁ and DP₂,but the DP₁ receptor is expressed at lower levels. In agreement withthis, the chemotaxis of human peripheral blood eosinophils is inhibitedby both DP₁ and DP₂ antagonists. Accordingly, DP₁, DP₂ and dual DP₁/DP₂antagonists are useful in the treatment of allergic inflammation.

Activation of DP₂ is associated with chemotaxis and activation of Th2lymphocytes, eosinophils and basophils. In particular, PGD₂ binds to DP₂and mediates many of its effects through a G₁-dependent elevation ofintracellular calcium levels and reduction of cyclic AMP. In Th2lymphocytes, IL4, IL5 and IL13 cytokine production are also stimulatedby DP₂ activation. These cytokines have been implicated in numerousbiological actions including, by way of example only, immunoglobulin Eproduction, airway response, mucous secretion, and eosinophilrecruitment.

The terms CRTH2 and DP₂, refer to the same receptor and are usedinterchangeably herein. Likewise, another common name for DP is DP₁, andthe two terms are used interchangeably herein.

Illustrative Biological Activity

Prostaglandins (PGs) are recognized physiological lipid acid mediatorsproduced by the release of arachidonic acid from cell membranephospholipids and converted to prostaglandins by the action of COX₁ andCOX₂ cyclooxygenases and PG synthases. The cyclooxygenases sequentiallyconvert arachidonic acid to cyclic endoperoxide prostaglandin G₂ (PGG₂)and subsequently, prostaglandin H₂ (PGH₂). Depending on the tissue,physiological signal, and/or synthase type, PGH₂ can be converted tonumerous different prostaglandins, such as PGE₂, PGD₂, PGF₂α, and PGI₂as well as thromboxane A₂, another eicosanoid signaling molecule. Thesemediators then elicit a wide variety of physiological responsesincluding vasoconstriction or dilation, platelet aggregation, calciumtransport, pain sensitization, hormone release, inflammatory and immuneresponse, and cellular growth.

Prostaglandin D₂ is a major metabolite produced from the PGH₂intermediate via hematopoietic PGD₂ synthase or lipocalin PGD₂ synthase.In the brain and central nervous system, PGD₂ is produced and thought tofunction in pain perception and sleep regulation. In other tissues, PGD₂is produced primarily in immunoglobulin E (IgE) activated mast cells andto a lesser extent, in macrophages, dendritic cells, T helper 2 (Th2)lymphocytes and other leukocytes. In the cell, PGD₂ is rapidlymetabolized and converted to other downstream effectors includingΔ¹²PGJ₂, 9α11βPGF₂, 13,14-dihydro-15-keto-PGD₂, and15-deoxy-Δ^(12,14)PGD₂.

Mast-cell-derived PGD₂ is produced in high concentrations in response toan allergen challenge. Studies in preclinical species have observed thefollowing features when PGD₂ is applied to in vivo preparations, or itsoverproduction is engineered by genetic manipulation:

-   -   Vasodilatation leading to erythema (flare) and -potentiation of        oedema (wheal).    -   Recruitment of eosinophils and Th2 lymphocytes.    -   Modulation of Th2-cytokine production.    -   Bronchoconstriction.

Injection of PGD₂ into human skin has been shown to produce a longlasting erythema, to potentiate the effects of other mediators oninduration and leukocyte infiltration in human skin and to enhanceoedema formation in rat skin. It is most likely that these effects ofPGD₂, like those of other vasodilator prostaglandins, are due to anincreased blood flow to the inflamed lesion and are, therefore, mostlikely to be mediated predominantly by the DP₁ receptor. Although theseobservations make it clear that DP₁ mediates the vascular effects ofPGD₂, the capacity of PGD₂ to promote the cellular changes associatedwith inflammation is not due to an action on DP₁.

The main receptors that are activated by PGD₂ or its metabolites andmediate its effects are DP₁, CRTH2 (or DP₂) and TP.

DP₁ (or DP) is a G-protein coupled seven-transmembrane receptor that,upon activation by PGD₂ binding, leads to an increase in intracellularcAMP levels. DP₁ is expressed in the brain, bronchial smooth muscle,vascular and airway smooth muscle, dendritic cells, and platelets andinduces PGD₂ dependent bronchodilation, vasodilation, plateletaggregation inhibition, and suppression of cytokine production. Geneticanalysis of DP₁ function using knock-out mice has shown that micelacking DP do not develop asthmatic responses in an ovalbumin-inducedasthma model. Analysis of selective DP antagonists in guinea pigallergic rhinitis models demonstrated dramatic inhibition of early nasalresponses, as assessed by sneezing, mucosal plasma exudation andeosinophil infiltration. DP antagonism alleviates allergen-inducedplasma exudation in the conjunctiva in a guinea pig allergicconjuctivitis model and antigen-induced eosinophil infiltration into thelung in a guinea pig asthma model.

Much of the pro-inflammatory activity of PGD₂ is through interactionwith DP₂ (or CRTH2). DP₂ is a G-protein coupled receptor and istypically highly expressed in Th2 lymphocytes, eosinophils andbasophils. DP₂ activation functions to directly activate and recruit Th2lymphocytes and eosinophils. Activated Th2 lymphocytes produce andsecrete inflammatory cytokines including IL4, IL5, and IL13. Despitebinding PGD₂ with a similar affinity as DP₁, DP₂ is not structurallyrelated to DP₁ and signals through a different mechanism—the effects ofDP₂ are mediated through Gi-dependent elevation in intracellular calciumlevels and reduction in intracellular levels of cyclic AMP. DP₂activation is important in eosinophil recruitment in response toallergic challenge in such tissues as nasal mucosa, bronchial airways,and skin. The application of either PGD₂ or selective DP₂ agonists bothexacerbate and enhance allergic responses in lung and skin. DP₂activation appears to have a crucial role in mediating allergicresponses, and thus the use of antagonists of PGD₂ activation of the DP₂receptor are an attractive approach to treat the inflammatory componentof allergic diseases such as asthma, rhinitis, and dermatitis.

TP receptors primarily function to antagonize DP₁ receptor's effectssuch as promoting bronchoconstriction, vasoconstriction, and plateletaggregation. While TP receptor's main ligand is thromboxane A₂, it alsobinds and is activated by the PGD₂ derivative, 9α11βPGF₂. TP is aGq-coupled prostanoid receptor that binds thromboxane with highaffinity, promoting platelet aggregation and constriction of bothvascular and airway smooth muscle. PGD₂ activates the TP receptor inhuman bronchial muscle, probably through the formation of the11-ketoreductase metabolite 9α11βPGF2. The bronchoconstrictor effects ofTP dominate over the bronchodilator effects of DP₁ in the airways.

DP₁ and DP₂ have crucial, and complementary, roles in the physiologicalresponse of animals to PGD₂ and blockade of either one or both of thesereceptors may prove beneficial in alleviating allergic diseases orconditions triggered by PGD₂, such as, but not limited to, allergicrhinitis, asthma, dermatitis, and allergic conjunctivitis.

Presented herein are compounds, pharmaceutical compositions andmedicaments, methods, for (a) diagnosing, preventing, or treatingallergic and non-allergic inflammation, (b) mitigating adverse signs andsymptoms that are associated with inflammation, and/or (c) controllingimmunological, proliferative or metabolic disorders. These disorders mayarise from one or more of a genetic, iatrogenic, immunological,infectious, metabolic, oncological, toxic, surgical, and/or traumaticetiology. In one aspect, the methods, compounds, pharmaceuticalcompositions, and medicaments described herein comprise antagonists ofPGD₂ receptors. In one aspect, the methods, compounds, pharmaceuticalcompositions, and medicaments described herein comprise antagonists ofDP₂.

In some embodiments provided herein are compounds of Formula (I),pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs,and pharmaceutically acceptable solvates thereof, which are antagonistsof DP₂, and are used to treat subjects suffering from one or morePGD₂-dependent conditions or diseases, including, but not limited to,asthma, rhinitis, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis,inflammatory bowel disease, adult respiratory distress syndrome,myocardial infarction, aneurysm, stroke, cancer, endotoxic shock,proliferative disorders and inflammatory conditions. In someembodiments, PGD₂-dependent conditions or diseases include those whereinan absolute or relative excess of PGD₂ is present and/or observed.

Compounds

Compounds of any of Formula (I), Formula (II), or Formula (III)including pharmaceutically acceptable salts, pharmaceutically acceptableprodrugs, and pharmaceutically acceptable solvates thereof, antagonizeor modulate DP₂ and are used to treat subjects suffering fromPGD₂-dependent or PGD₂ mediated conditions or diseases, including, butnot limited to, asthma, rhinitis, dermatitis, and inflammatoryconditions.

In some embodiments provided herein is a compound having the structureof Formula (I), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof:

wherein,

R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN,—NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —S(═O)₂N(R¹³)₂,—NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³, —OCO₂R¹², —N(R¹³)₂,—C(═O)N(R¹³)₂, —OC(═O)N(R¹³)₂, —NHC(═O)R¹², —NHC(═O)OR¹², C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, anoptionally substituted cycloalkyl, an optionally substitutedheterocycloalkyl, optionally substituted phenyl, and an optionallysubstituted monocyclic heteroaryl;

-   -   R⁵ is L⁵-X⁵;        -   L⁵ is —C₁-C₆alkyl-, —C₁-C₆flouroalkyl-, or            —C₃-C₆cycloalkyl-, an optionally substituted            —C₁-C₆alkyl-aryl, an optionally substituted            —C₁-C₆alkyl-heteroaryl, an an optionally substituted aryl,            or an optionally substituted heteroaryl;        -   X⁵ is a polar substituent;    -   R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocycloalkyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted        —C₁-C₆alkyl-cycloalkyl, an optionally substituted        —C₁-C₆alkyl-heterocycloalkyl, an optionally substituted        —C₁-C₆alkyl-aryl, or an optionally substituted        —C₁-C₆alkyl-heteroaryl;    -   R⁷ is L⁷-X⁷;        -   L⁷ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, or an optionally            substituted C₃-C₆cycloalkyl;        -   X⁷ is —CO₂H, —CO₂R¹², —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂,            —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹²,            —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹²,            —OH, —OR¹², —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂,            —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or            —C(═NR¹⁴)N(R¹³)₂;    -   each R⁸ and R⁹ is independently selected from H, C₁-C₄alkyl, and        C₁-C₄haloalkyl;    -   two R⁸ groups are taken together with the carbon atom to which        they are attached to form a carbonyl (—C(═O)—);    -   both R⁹ groups are taken together with the carbon atom to which        they are attached to form a carbonyl (—C(═O)—);    -   R¹⁰ is H, C₁-C₄alkyl, C₁-C₄haloalkyl, or -L¹⁰-X¹⁰;        -   L¹⁰- is —C₁-C₆alkyl-, or —C₃-C₆cycloalkyl-, an optionally            substituted —C₁-C₆alkyl-aryl or an optionally substituted            —C₁-C₆alkyl-heteroaryl;        -   X¹⁰ is —CO₂R¹³, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH,            —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂,            —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OR¹³, —SR¹²,            —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹²,            —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂;    -   R¹² is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, optionally        substituted benzyl or optionally substituted heteroaryl;    -   each R¹³ is independently selected from H, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, an optionally substituted        cycloalkyl, an optionally substituted heterocycloalkyl, an        optionally substituted aryl, an optionally substituted benzyl,        and an optionally substituted heteroaryl;    -   two R¹³ groups attached to the same N atom are taken together        with the N atom to which they are attached to form an optionally        substituted heterocycloalkyl;    -   R¹⁴ is selected from among H, —S(═O)₂R¹², —S(═O)₂NH₂, —C(═O)R¹²,        —CN, and —NO₂;    -   m is 1, 2, or 3.

For any and all of the embodiments, substituents can be selected fromamong from a subset of the listed alternatives. For example, in someembodiments, m is 1 or 2. In some embodiments, m is 1. In someembodiments, m is 2.

In some embodiments, X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹²,—C(═O)N(R¹³)₂, —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹²,—S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹³,—SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹²,—SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂. In someembodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂,—C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂,—NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹³, —SR¹², —S(═O)R¹²,—S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹²,—SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂. In some embodiments, X⁵ is—CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂,—NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —SR¹², —S(═O)R¹², —S(═O)₂R¹², or—N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂,—NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, or—N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂,—S(═O)₂N(R¹³)₂, or —OH.

In some embodiments, each R⁸ and R⁹ is each independently selected fromH, or —CH₃; or two R⁸ groups are taken together with the carbon atom towhich they are attached to form a carbonyl(-C(═O)—); or both R⁹ groupsare taken together with the carbon atom to which they are attached toform a carbonyl(-C(═O)—); and m is 1 or 2.

In some embodiments, R¹, R², R³, and R⁴ each are independently selectedfrom H, halogen, —CN, —NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹²,—S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³,—OCO₂R¹², —N(R¹³)₂, —C(═O)N(R¹³)₂, —OC(═O)N(R¹³)₂, —NHC(═O)R¹²,—NHC(═O)OR¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, C₁-C₆heteroalkyl, an optionally substituted cycloalkyl, anoptionally substituted heterocycloalkyl, optionally substituted phenyl,and an optionally substituted monocyclic heteroaryl, provided that atleast two of R¹, R², R³, and R⁴ are H.

In some embodiments, R¹, R², R³, and R⁴ each are independently selectedfrom H, halogen, —CN, —OH, —OR¹³, —S(═O)₂C₁-C₆alkyl, —S(═O)₂N(R¹³)₂,—NHS(═O)₂R¹², —OC(═O)R¹², —C(═O)N(R¹³)₂, —NHC(═O)R¹², C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments, R¹, R², R³, and R⁴ each are independently selectedfrom H, halogen, —CN, —OH, —OR¹³, —S(═O)₂C₁-C₆alkyl, —S(═O)₂N(R¹³)₂,—NHS(═O)₂R¹², —OC(═O)R¹², —C(═O)N(R¹³)₂, —NHC(═O)R¹², C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl,provided that at least two of R¹, R², R³, and R⁴ are H.

In some embodiments, R⁶ is C₁-C₆alkyl, C₁-C₆ fluoroalkyl,C₁-C₆heteroalkyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocycloalkyl, an optionally substituted phenyl, anoptionally substituted naphthyl, an optionally substituted heteroarylcontaining 0-3 N atoms, an optionally substituted—C₁-C₆alkyl-cycloalkyl, an optionally substituted—C₁-C₆alkyl-heterocycloalkyl, an optionally substituted—C₁-C₆alkyl-phenyl, or an optionally substituted —C₁-C₆alkyl-heteroaryl.

In some embodiments, L⁷ is C₁-C₆alkyl, C₁-C₆ fluoroalkyl, or anoptionally substituted C₃-C₆cycloalkyl; X⁷ is —CO₂R¹³, —C(═O)N(R¹³)₂,tetrazolyl, —OH, or —C(═O)NHC(═O)R¹². In some embodiments, L¹ isC₁-C₆alkyl.

In some embodiments, L⁵ is —C₁-C₆alkyl, or an optionally substituted—C₁-C₆alkyl-phenyl; and X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹²,—C(═O)N(R¹³)₂, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹²,—NHC(═O)R¹², —OH, —OR¹³, —S(═O)R¹², —S(═O)₂R¹², or —N(R¹³)₂. In someembodiments, L⁵ is —C₁-C₆alkyl.

In some embodiments, R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, an optionally substituted C₃-C₁₀cycloalkyl, anoptionally substituted phenyl, an optionally substituted naphthyl, anoptionally substituted monocyclic heteroaryl containing 0-3 N atoms, anoptionally substituted —C₁-C₆alkyl-cycloalkyl, an optionally substituted—C₁-C₆alkyl-phenyl, or an optionally substituted —C₁-C₆alkyl-(monocyclicheteroaryl).

In some embodiments, L⁵ is C₁-C₆alkyl; X⁵ is F, —CO₂R¹³, —CN,—C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂,—NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —OR¹³, —SR¹², —S(═O)₂, or —N(R¹³)₂. Insome embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —NHS(═O)₂R¹²,—S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —S(═O)₂R¹², or—N(R¹³)₂.

In some embodiments, L⁷ is C₁-C₆alkyl; X⁷ is CO₂H, —CO₂(C₁-C₆alkyl), or—OH. In some embodiments, X⁷ is CO₂H, or —OH.

In some embodiments, R¹⁰ is H or C₁-C₄alkyl.

In some embodiments, each of R⁸ and R⁹ is H.

In some embodiments, the compound of Formula (I) has the followingstructure:

In some embodiments, m is 1.

In some embodiments, the compound of Formula (I) has the structure ofFormula (II):

In some embodiments, m is 2.

In some embodiments, the compound of Formula (I) has the structure ofFormula (III):

In some embodiments, R¹⁰ is H or —CH₃. In some embodiments, R¹⁰ is H.

In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —OH, or —OR¹³.In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, or —OH.

In some embodiments, R¹, R², R³, and R⁴ each are independently selectedfrom H, F, Cl, Br, I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and —CF₃; andR¹⁰ is H. In some embodiments, R¹, R², R³, and R⁴ each are independentlyselected from H, F, Cl, Br, I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and—CF₃, provided that at least two of R¹, R², R³, and R⁴ are H. In someembodiments, each of R¹, R², R³, and R⁴ are H.

In some embodiments, R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, an optionally substituted phenyl, an optionallysubstituted naphthyl, or an optionally substituted monocyclic heteroarylcontaining 0-3 N atoms. In some embodiments, R⁶ is C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, or an optionally substituted phenyl.In some embodiments, R⁶ is an optionally substituted phenyl.

In some embodiments, R⁷ is —CH₂CO₂H, —CH₂CH₂CO₂H, —C(CH₃)₂OH,—CH₂C(CH₃)₂OH, or —CH₂CH₂C(CH₃)₂OH.

In some embodiments, R⁵ is —CH₂CO₂H, —CH₂C(CH₃)₂OH, or —CH₂C(═O)NH₂.

Any combination of the groups described above for the various variablesis contemplated herein.

In some embodiments, the compounds of any of Formula (I), Formula (II),or Formula (III), include, but are not limited to:

Compound No. R⁷ R⁵ R⁶ 1-1 —CH₂CO₂H —CH₂CO₂H 4-fluorophenyl 1-2—CH₂CH₂C(CH₃)₂OH —CH₂CO₂H 4-fluorophenyl 1-3 —CH₂CH₂CO₂H —CH₂C(CH₃)₂OH4-fluorophenyl 1-4 —CH₂CH₂C(CH₃)₂OH —CH₂C(CH₃)₂OH 4-fluorophenyl 1-5—CH₂CH₂CO₂H —CH₂C(═O)NH₂ 4-fluorophenyl 1-6 —CH₂CH₂CO₂H —CH₂CO₂H4-fluorophenylSynthesis of Compounds

Compounds of Formula (I), Formula (II), and Formula (III) described inthe prior section are synthesized using standard synthetic techniques orusing methods known in the art in combination with methods describedherein. In additions, solvents, temperatures and other reactionconditions presented herein may vary.

The starting material used for the synthesis of the compounds of Formula(I), Formula (II), and Formula (III) described in the prior section areeither synthesized or obtained from commercial sources, such as, but notlimited to, Aldrich Chemical Co. (Milwaukee, Wis.), or Sigma ChemicalCo. (St. Louis, Mo.). The compounds described herein, and other relatedcompounds having different substituents are synthesized using knowntechniques and materials, including those found in March, ADVANCEDORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg, ADVANCEDORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), andGreen and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed.,(Wiley 1999). General methods for the preparation of compounds can bemodified by the use of appropriate reagents and conditions for theintroduction of the various moieties found in the formulae as providedherein.

In one aspect, compounds of Formula (I) have the structure of Formula1-IV. In one aspect, compounds of general structure 1-IV are prepared asoutlined in Scheme 1.

Amine 1-I (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989, 39, p1519; in racemic, (+)- or (−)-form) is reacted with a sulfonyl chloridein the presence of a base and a solvent to produce 1-II. In one aspectthe base is Et₃N. In one aspect, the solvent is an organic solvent (e.g.THF). Deprotonation of the indole N—H of 1-II using a strong base andsubsequent alkylation with an electrophile R⁷—X yields 1-III. A secondalkylation using R⁵—X then allows for N-alkylation of the sulfonamide togive 1-IV. Treatment of 1-II with an excess of strong base followed bydouble alkylation will provide 1-IV in which R⁵ and R⁷ are the same.

In one aspect, indoles of structure 1-II are alkylated as shown inScheme 2.

Indoles of structure 1-II are N-alkylated using NaH and acrylonitrile inTHF (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989, 39, p 1519;Scheme 2) to provide compounds of structure 2-II. Hydrolysis of thenitrile then affords 2-II. Treatment of 2-H with excess base, such asNaH, in a solvent, such as DMF, followed by alkylation of thesulfonamide then yields the bis-alkylated product 2-III. Aqueoushydrolysis of compounds of structure 2-III then provides compounds ofstructure 2-IV.

In one aspect, compounds of structure 2-III are derivatized as outlinedin Scheme 3.

Compounds of structure 2-III (Scheme 3; R⁵ is —CH₂CO₂Me) are furtherderivatized by reaction with a Grignard reagent or alkyl lithium reagentin a solvent such as THF. Subsequent treatment with aqueous base (e.g.LiOH) of the crude product and separation using standard methodologiessuch as HPLC allows for the preparation of compounds 3-II, 3-III, and3-IV.

In one aspect, compounds of structure 2-II are further derivatived asoutlined in Scheme 4.

Reaction of compounds of structure 2-II with R⁵-X provides compounds ofstructure 4-I. In one aspect, R⁵—X is bromo acetonitrile. Reaction ofcompounds of structure 4-I (R⁵ is —CH₂CN) with concentrated HCl in asolvent such as methanol followed by base hydrolysis to yield the amidesof structure 4-II.

In one aspect, the compound of Formula (I) has a structure of Formula1-IV. In one aspect, the compound of Formula (I) has a structure ofFormula 2-III. In one aspect, the compound of Formula (I) has astructure of Formula 2-IV. In one aspect, the compound of Formula (I)has a structure of Formula 3-II. In one aspect, the compound of Formula(I) has a structure of Formula 3-III. In one aspect, the compound ofFormula (I) has a structure of Formula 4-I. In one aspect, the compoundof Formula (I) has a structure of Formula 4-II.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

In certain embodiments, the compounds described herein are modifiedusing various electrophiles or nucleophiles to form new functionalgroups or substituents. Table 1 entitled “Examples of Covalent Linkagesand Precursors Thereof” lists selected, non-limiting examples ofcovalent linkages and precursor functional groups that are used toprepare the modified compounds. Precursor functional groups are shown aselectrophilic groups and nucleophilic groups.

TABLE 1 Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes orketones Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkylamines alkyl halides amines/anilines Esters alkyl halides carboxylicacids Thioethers alkyl halides Thiols Ethers alkyl halidesalcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkylsulfonates carboxylic acids Ethers alkyl sulfonates alcohols/phenolsEsters Anhydrides alcohols/phenols Carboxamides Anhydridesamines/anilines Thiophenols aryl halides Thiols Aryl amines aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides carboxylic acids amines/anilines Esters carboxylic acidsAlcohols hydrazines Hydrazides carboxylic acids N-acylureas orAnhydrides carbodiimides carboxylic acids Esters diazoalkanes carboxylicacids Thioethers Epoxides Thiols Thioethers haloacetamides ThiolsAmmotriazines halotriazines amines/anilines Triazinyl ethershalotriazines alcohols/phenols Amidines imido esters amines/anilinesUreas Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenolsThioureas isothiocyanates amines/anilines Thioethers Maleimides ThiolsPhosphite esters phosphoramidites Alcohols Silyl ethers silyl halidesAlcohols Alkyl amines sulfonate esters amines/anilines Thioetherssulfonate esters Thiols Esters sulfonate esters carboxylic acids Etherssulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilinesSulfonate esters sulfonyl halides phenols/alcoholsUse of Protecting Groups

In the reactions described, it is necessary in certain embodiments toprotect reactive functional groups, for example hydroxy, amino, imino,thio or carboxy groups, where these are desired in the final product, toavoid their unwanted participation in the reactions. Protecting groupsare used to block some or all reactive moieties and prevent such groupsfrom participating in chemical reactions until the protective group isremoved. In one embodiment, each protective group is removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval. In some embodiments, protective groups are removed by acid,base, and/or hydrogenolysis. Groups such as trityl, dimethoxytrityl,acetal and t-butyldimethylsilyl are acid labile and are used in certainembodiments to protect carboxy and hydroxy reactive moieties in thepresence of amino groups protected with Cbz groups, which are removableby hydrogenolysis, and/or Fmoc groups, which are base labile. In otherembodiments, carboxylic acid and hydroxy reactive moieties are blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

In another embodiment, carboxylic acid and hydroxy reactive moieties areblocked with hydrolytically removable protective groups such as thebenzyl group, while amine groups capable of hydrogen bonding with acidsare blocked with base labile groups such as Fmoc. In another embodiment,carboxylic acid reactive moieties are protected by conversion to simpleester compounds as exemplified herein, or they are, in yet anotherembodiment, blocked with oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups are blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd(0)-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate is attached. As long as theresidue is attached to the resin, that functional group is blocked andcannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups are, by way of example only:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure.

In certain embodiments, compounds are prepared using standard proceduressuch as those found in Katritzky, “Handbook of Heterocyclic Chemistry”Pergamon Press, Oxford, 1986; Pindur et al, J. Heterocyclic Chem., vol25, 1, 1987, and Robinson “The Fisher Indole Synthesis”, John Wiley &Sons, Chichester, N.Y., 1982, are incorporated herein by reference forsuch disclosure.

Further Forms of Compounds

In certain embodiments, compounds of any of Formula (I), Formula (II),or Formula (III), are prepared as a pharmaceutically acceptable acidaddition salt (which is a type of a pharmaceutically acceptable salt) byreacting the free base form of the compound with a pharmaceuticallyacceptable inorganic or organic acid, including, but not limited to,inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid metaphosphoric acid, and the like;and organic acids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, and muconic acid.

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, pharmaceuticallyacceptable salts are obtained by reacting a compound of any of Formula(I), Formula (II), or Formula (III), with acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like. Pharmaceutically acceptable salts are alsoobtained by reacting a compound of any of Formula (I), Formula (II), orFormula (III), with a base to form a salt such as an ammonium salt, analkali metal salt, such as a sodium or a potassium salt, an alkalineearth metal salt, such as a calcium or a magnesium salt, a salt oforganic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, and salts with amino acids such asarginine, lysine, and the like.

In other embodiments, compounds of any of Formula (I), Formula (II), orFormula (III), are prepared as a pharmaceutically acceptable salts byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base, including, but not limited toorganic bases such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like, or with an inorganic basesuch as aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and areoptionally formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol. Solvates of compounds of any ofFormula (I), Formula (II), or Formula (III), are conveniently preparedor formed during the processes described herein. By way of example only,hydrates of compounds of any of Formula (I), Formula (II), or Formula(III), are conveniently prepared by recrystallization from anaqueous/organic solvent mixture, using organic solvents including, butnot limited to, dioxane, tetrahydrofuran, ethanol, or methanol. Inaddition, the compounds provided herein can exist in unsolvated as wellas solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

In yet other embodiments, the compounds of any of Formula (I), Formula(II), or Formula (III), are prepared in various forms, including but notlimited to, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds of any of Formula (I), Formula (II), or Formula(III), include crystalline forms, also known as polymorphs. Polymorphsinclude the different crystal packing arrangements of the same elementalcomposition of a compound. Polymorphs usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. Various factors such as the recrystallization solvent,rate of crystallization, and storage temperature may cause a singlecrystal form to dominate.

In some embodiments, compounds of any of Formula (I), Formula (II), orFormula (III), are prepared as prodrugs. A “prodrug” refers to an agentthat is converted into the parent drug in vivo. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the parent drug. They may, for instance, be bioavailable by oraladministration whereas the parent is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.An example, without limitation, of a prodrug would be a compound of anyof Formula (I), Formula (II), or Formula (III), which is administered asan ester (the “prodrug”) to facilitate transmittal across a cellmembrane where water solubility is detrimental to mobility but whichthen is metabolically hydrolyzed to the carboxylic acid, the activeentity, once inside the cell where water-solubility is beneficial. Afurther example of a prodrug might be a short peptide (polyaminoacid)bonded to an acid group where the peptide is metabolized to reveal theactive moiety.

Prodrugs are generally drug precursors that, following administration toa subject and subsequent absorption, are converted to an active, or amore active species via some process, such as conversion by a metabolicpathway. Some prodrugs have a chemical group present on the prodrug thatrenders it less active and/or confers solubility or some other propertyto the drug. Once the chemical group has been cleaved and/or modifiedfrom the prodrug the active drug is generated. Prodrugs are often usefulbecause, in some situations, they are easier to administer than theparent drug. In certain embodiments, the prodrug of a compound describedherein is bioavailable by oral administration whereas the parent is not.Furthermore, in some embodiments, the prodrug of a compound describedherein has improved solubility in pharmaceutical compositions over theparent drug.

In other embodiments, prodrugs are designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In specific embodiments, the design of prodrugsto date is to increase the effective water solubility of the therapeuticcompound for targeting to regions where water is the principal solvent.Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al.,Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom.,6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37,87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988);Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V.Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S.Symposium Series; and Edward B. Roche, Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, 1987.

Additionally, prodrug derivatives of compounds of any of Formula (I),Formula (II), or Formula (III), are prepared, if desired (e.g., forfurther details see Saulnier et al., (1994), Bioorganic and MedicinalChemistry Letters, Vol. 4, p. 1985). By way of example only, in oneaspect appropriate prodrugs are prepared by reacting a non-derivatizedcompound of any of Formula (I), Formula (II), or Formula (III), with asuitable carbamylating agent, such as, but not limited to,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike. Prodrug forms of the herein described compounds, wherein theprodrug is metabolized in vivo to produce a derivative as set forthherein are included within the scope of the claims. Indeed, some of theherein-described compounds are a prodrug for another derivative oractive compound.

In some embodiments, sites on the aromatic ring portion of compounds ofany of Formula (I), Formula (II), or Formula (III), are susceptible tovarious metabolic reactions Therefore incorporation of appropriatesubstituents on the aromatic ring structures will reduce, minimize oreliminate this metabolic pathway. In specific embodiments, theappropriate substituent to decrease or eliminate the susceptibility ofthe aromatic ring to metabolic reactions is, by way of example only, ahalogen, or an alkyl group.

In another embodiment, the compounds described herein are labeledisotopically or by another other means, including, but not limited to,the use of chromophores or fluorescent moieties, bioluminescent labels,or chemiluminescent labels. In some embodiments, compounds describedherein are isotopically-labeled, which are identical to those recited inthe various formulae and structures presented herein, but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. In some embodiments, one or more hydrogen atoms are replacedwith deuterium. In some embodiments, metabolic sites on the compoundsdescribed herein are deuterated. In some embodiments, substitution withdeuterium affords certain therapeutic advantages resulting from greatermetabolic stability, such as, for example, increased in vivo half-lifeor reduced dosage requirements.

In yet another embodiment, the compounds of any of Formula (I), Formula(II), or Formula (III), possess one or more stereocenters and eachcenter exists independently in either the R or S configuration. Thecompounds presented herein include all diastereomeric, enantiomeric, andepimeric forms as well as the appropriate mixtures thereof. In certainembodiments, compounds of any of Formula (I), Formula (II), or Formula(III), are prepared as their individual stereoisomers by reacting aracemic mixture of the compound with an optically active resolving agentto form a pair of diastereoisomeric compounds, separating thediastereomers and recovering the optically pure enantiomers. In someembodiments, resolution of enantiomers is carried out using covalentdiastereomeric derivatives of the compounds described herein. In otherembodiments, dissociable complexes are utilized (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and are, in specific embodiments, separated by taking advantage of thesedissimilarities. In these embodiments, the diastereomers are separatedby chiral chromatography or by separation/resolution techniques basedupon differences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatdoes not result in racemization. Jean Jacques, Andre Collet, Samuel H.Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons,Inc., 1981.

Additionally, in certain embodiments, the compounds provided hereinexist as geometric isomers. The compounds and methods provided hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof. In someembodiments, the compounds described herein exist as tautomers. Alltautomers are intended to be within the scope of the molecular formulasdescribed herein. In additional embodiments of the compounds and methodsprovided herein, mixtures of enantiomers and/or diastereoisomers,resulting from a single preparative step, combination, orinterconversion are envisioned.

Certain Chemical Terminology

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. In this application, the use of “or” or “and”means “and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as “include”, “includes,” and“included,” is not limiting.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety may be a saturated alkyl group, which means that it does notcontain any units of unsaturation (e.g. carbon-carbon double bonds orcarbon-carbon triple bonds). The alkyl moiety may also be an unsaturatedalkyl moiety, which means that it contains at least one unit ofunsaturation. The alkyl moiety, whether saturated or unsaturated, may bebranched, straight chain, or cyclic. The point of attachment of an alkylis at a carbon atom that is not part of a ring.

The “alkyl” moiety has between 1 to 10 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupmay consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., upto and including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₄ alkyl” or similar designations. By way of exampleonly, “C₁-C₄ alkyl” indicates that there are one to four carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, and t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, pentyl, neopentyl, hexyl, allyl, but-2-enyl, but-3-enyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, and the like. In one aspect, an alkyl is a C₁-C₆alkyl.

An “amide” is a chemical moiety with formula —C(═O)NHR or —NHC(═O)R,where R is selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic(bonded through a ring carbon). An amide may be an amino acid or apeptide molecule attached to a compound of Formula (I), Formula (II), orFormula (III) thereby forming a prodrug. Any amine, or carboxyl sidechain on the compounds described herein is optionally amidified, asdesired. See, e.g., Greene and Wuts, Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999, isincorporated herein by reference for such disclosure.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, ten, ormore than ten atoms. Aromatics are optionally substituted. The term“aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) andheterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g.,pyridine). The term includes monocyclic or fused-ring polycyclic (i.e.,rings which share adjacent pairs of carbon atoms) groups.

The term “carbocyclic” refers to a ring or ring system where the atomsforming the backbone of the ring are all carbon atoms. The term thusdistinguishes carbocyclic from heterocyclic rings in which the ringbackbone contains at least one atom which is different from carbon.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings are formed byfive, six, seven, eight, nine, or more than nine carbon atoms. In oneaspect, an aryl is a C₆-C₁₀aryl. Aryl groups are optionally substituted.Examples of aryl groups include, but are not limited to phenyl, andnaphthalenyl. In some embodiments, an awl is a phenyl. Depending on thestructure, an awl group can be a monoradical or a diradical (i.e., anarylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, orpartially unsaturated. Cycloalkyls may be fused with an aromatic ring,and the point of attachment is at a carbon that is not an aromatic ringcarbon atom. Cycloalkyl groups include groups having from 3 to 10 ringatoms. Illustrative examples of cycloalkyl groups include, but are notlimited to, the following moieties:

and the like. In some embodiments, cycloalkyl groups are selected fromamong cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. In some embodiments, bicyclic cycloalkyl groups are selectedfrom among indanyl, indenyl, and 1,2,3,4-tetrahydronaphthalenyl.Cycloalkyl groups may be substituted or unsubstituted. Depending on thestructure, a cycloalkyl group can be a monoradical or a diradical (i.e.,an cycloalkylene group, such as, but not limited to,cyclopropan-1,1-diyl, cyclobutan-1,1-diyl, cyclopentan-1,1-diyl,cyclohexan-1,1-diyl, cycloheptan-1,1-diyl, and the like).

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). Any hydroxy, or carboxyl side chain on thecompounds described herein is esterified, if desired. Examples ofprocedures and specific groups to make such esters are found in sourcessuch as Greene and Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley & Sons, New York, N.Y., 1999.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo.

The term “haloalkyl” refers to an alkyl group in which one or morehydrogen atoms are replaced by one or more halide atoms. In one aspect,a haloalkyl is a C₁-C₆haloalkyl.

The term “fluoroalkyl” refers to a alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆fluoroalkyl. Examples of fluoroalkyls include, —CF₃, —CHF₂, —CH₂F,—CH₂CF₃ and —CF₂CF₃.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Inone aspect, a heteroalkyl is a C₁-C₆ heteroalkyl. In some embodiments,heteroalkyl refers to an alkyl group in which one of the skeletal atomsof the alkyl is oxygen or nitrogen.

The term “heterocycle” refers to heteroaromatic and heteroalicyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the ring of said group does notcontain two adjacent O or S atoms. Non-aromatic heterocyclic groupsinclude groups having only 3 atoms in their ring system, but aromaticheterocyclic groups must have at least 5 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems. An example of a3-membered heterocyclic group is aziridinyl. An example of a 4-memberedheterocyclic group is azetidinyl. An example of a 5-memberedheterocyclic group is thiazolyl. An example of a 6-membered heterocyclicgroup is pyridyl, and an example of a 10-membered heterocyclic group isquinolinyl. Examples of non-aromatic heterocyclic groups arepyrrolidinyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrothienyl,oxazolidinonyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,futyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles may besubstituted with one or two oxo (═O) moieties, such as pyrrolidin-2-one.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude the following moieties:

and the like. An N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. In one aspect, the heteroaryl is aC₁-C₁₀heteroaryl. In another aspect, the heteroaryl is aC₂-C₉heteroaryl. In some cases, the heteroaryl includes at least one Natom in the ring. In one aspect, monocyclic heteroaryl is aC₁-C₅heteroaryl. In one aspect, bicyclic heteroaryl is aC₅-C₁₀heteroaryl.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup that includes at least one heteroatom selected from nitrogen,oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl.Illustrative examples of heterocycloalkyl groups, also referred to asnon-aromatic heterocycles, include:

and the like. In some embodiments, the heterocycloalkyl is selected fromoxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, and indolinyl. The term heteroalicyclicalso includes all ring forms of the carbohydrates, including but notlimited to the monosaccharides, the disaccharides and theoligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “membered ring” includes any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridinyl, pyranyland thiopyranyl are 6-membered rings and cyclopentyl, pyrrolyl, furanyl,and thiophenyl are 5-membered rings.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,cyano, halo, carbonyl, thiocarbonyl, nitro, haloalkyl, fluoroalkyl, andamino, including mono- and di-substituted amino groups, and theprotected derivatives thereof. By way of example an optionalsubstituents may be halide, —CN, —NO₂, or L_(s)R_(s), wherein each L_(s)is independently selected from a bond, —O—, —C(═O)—, —C(═O)O—, —S—,—S(═O)—, —S(═O)₂—, —NH—, —NHC(═O)—, —C(═O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(═O)NH—, —NHC(═O)O—, —(C₁-C₆ alkyl), or —(C₂-C₆ alkenyl); and eachR_(s) is independently selected from H, alkyl, fluoroalkyl, heteroalkyl,cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. The protecting groupsthat may form the protective derivatives of the above substituents maybe found in sources such as Greene and Wuts, above. In some embodiments,optional substituents are selected from halogen, —CN, —NH₂, —OH,—N(CH₃)₂, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, alkoxy, aryloxy, —S-alkyl, —S-aryl, —S(═O)-alkyl,—S(═O)-aryl, —S(═O)₂-alkyl, and —S(═O)₂-aryl. In some embodiments, anoptional substituents is F, Cl, Br, I, —CN, —NH₂, —OH, —NH(CH₃),—N(CH₃)₂, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, or —SO₂alkyl. In some embodiments, substituted groupsare substituted with one or more substituents selected from F, Cl, Br,—OH, —OCH₃, —CH₃, and —CF₃. In some embodiments, substituted groups aresubstituted with one of the preceding groups.

In certain embodiments, the compounds presented herein possess one ormore stereocenters and each center independently exists in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Stereoisomers are obtained, if desired, bymethods such as, the separation of stereoisomers by chiralchromatographic columns.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),solvates, or pharmaceutically acceptable salts of compounds having thestructure of any of Formula (I), Formula (II), or Formula (III) as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In specific embodiments, the compounds described herein exist insolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like. In other embodiments, the compounds describedherein exist in unsolvated form.

Certain Pharmaceutical and Medical Terminology

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator,” as used herein, refers to a molecule thatinteracts with a target either directly or indirectly. The interactionsinclude, but are not limited to, the interactions of an agonist, partialagonist, an inverse agonist and antagonist. In one embodiment, amodulator is an antagonist.

The term “agonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme activator or a hormone modulator that bindsto a specific receptor and triggers a response in the cell. An agonistmimics the action of an endogenous ligand (such as prostaglandin,hormone or neurotransmitter) that binds to the same receptor.

The term “antagonist,” as used herein, refers to a molecule such as acompound, which diminishes, inhibits, or prevents the action of anothermolecule or the activity of a receptor site. Antagonists include, butare not limited to, competitive antagonists, non-competitiveantagonists, uncompetitive antagonists, partial agonists and inverseagonists.

Competitive antagonists reversibly bind to receptors at the same bindingsite (active site) as the endogenous ligand or agonist, but withoutactivating the receptor.

Non-competitive antagonists (also known as allosteric antagonists) bindto a distinctly separate binding site from the agonist, exerting theiraction to that receptor via the other binding site. Non-competitiveantagonists do not compete with agonists for binding. The boundantagonists may result in a decreased affinity of an agonist for thatreceptor, or alternatively may prevent conformational changes in thereceptor required for receptor activation after the agonist binds.

Uncompetitive antagonists differ from non-competitive antagonists inthat they require receptor activation by an agonist before they can bindto a separate allosteric binding site.

Partial agonists are defined as drugs which, at a given receptor, mightdiffer in the amplitude of the functional response that they elicitafter maximal receptor occupancy. Although they are agonists, partialagonists can act as a competitive antagonist if co-administered with afull agonist, as it competes with the full agonist for receptoroccupancy and producing a net decrease in the receptor activationobserved with the full agonist alone.

An inverse agonist can have effects similar to an antagonist, but causesa distinct set of downstream biological responses. Constitutively activereceptors which exhibit intrinsic or basal activity can have inverseagonists, which not only block the effects of binding agonists like aclassical antagonist, but inhibit the basal activity of the receptor.

The term “PGD₂-dependent”, as used herein, refers to conditions ordisorders that would not occur, or would not occur to the same extent,in the absence of PGD₂.

The term “PGD₂-mediated”, as used herein, refers to refers to conditionsor disorders that might occur in the absence of PGD₂ but can occur inthe presence of PGD₂.

The term “asthma” as used herein refers to any disorder of the lungscharacterized by variations in pulmonary gas flow associated with airwayconstriction of whatever cause (intrinsic, extrinsic, or both; allergicor non-allergic). The term asthma may be used with one or moreadjectives to indicate cause.

The term “rhinitis” as used herein refers to any disorder of the nose inwhich there is inflammation of the mucous lining of the nose by whatevercause (intrinsic, extrinsic or both; allergic or non-allergic).

The term “bone disease,” as used herein, refers to a disease orcondition of the bone, including, but not limited to, inappropriate boneremodeling, loss or gain, osteopenia, osteomalacia, osteofibrosis, andPaget's disease.

The term “cardiovascular disease,” as used herein refers to diseasesaffecting the heart or blood vessels or both, including but not limitedto: arrhythmia (atrial or ventricular or both); atherosclerosis and itssequelae; angina; cardiac rhythm disturbances; myocardial ischemia;myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke;peripheral obstructive arteriopathy of a limb, an organ, or a tissue;reperfusion injury following ischemia of the brain, heart or other organor tissue; endotoxic, surgical, or traumatic shock; hypertension,valvular heart disease, heart failure, abnormal blood pressure; shock;vasoconstriction (including that associated with migraines); vascularabnormality, inflammation, insufficiency limited to a single organ ortissue.

The term “cancer,” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma)or hematological tumors (such as the leukemias).

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlesubject, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “dermatological disorder,” as used herein refers to a skindisorder. Such dermatological disorders include, but are not limited to,proliferative or inflammatory disorders of the skin such as, atopicdermatitis, bullous disorders, collagenoses, contact dermatitis eczema,Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The terms “fibrosis” or “fibrosing disorder,” as used herein, refers toconditions that follow acute or chronic inflammation and are associatedwith the abnormal accumulation of cells and/or collagen and include butare not limited to fibrosis of individual organs or tissues such as theheart, kidney, joints, lung, or skin, and includes such disorders asidiopathic pulmonary fibrosis and cryptogenic fibrosing alveolitis.

The term “iatrogenic” means a PGD₂-dependent or PGD₂-mediated condition,disorder, or disease created or worsened by medical or surgical therapy.

The term “inflammatory disorders” refers to those diseases or conditionsthat are characterized by one or more of the signs of pain, heat,redness, swelling, and loss of function (temporary or permanent).Inflammation takes many forms and includes, but is not limited to,inflammation that is one or more of the following: acute, adhesive,atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated,exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic,hypertrophic, interstitial, metastatic, necrotic, obliterative,parenchymatous, plastic, productive, proliferous, pseudomembranous,purulent, sclerosing, seroplastic, serous, simple, specific, subacute,suppurative, toxic, traumatic, and/or ulcerative. Inflammatory disordersfurther include, without being limited to those affecting the bloodvessels (polyarteritis, temporal arteritis); joints (arthritis:crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter's);gastrointestinal tract (colitis); skin (dermatitis); or multiple organsand tissues (systemic lupus erythematosus).

The term “immunological disorders” refers to those diseases orconditions that are characterized by inappropriate or deleteriousresponse to an endogenous or exogenous antigen that may result incellular dysfunction or destruction and consequently dysfunction ordestruction of an organ or tissue and which may or may not beaccompanied by signs or symptoms of inflammation.

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

The terms “neurodegenerative disease” or “nervous system disorder,” asused herein, refers to conditions that alter the structure or functionof the brain, spinal cord or peripheral nervous system, including butnot limited to Alzheimer's Disease, cerebral edema, cerebral ischemia,multiple sclerosis, neuropathies, Parkinson's Disease, those found afterblunt or surgical trauma (including post-surgical cognitive dysfunctionand spinal cord or brain stem injury), as well as the neurologicalaspects of disorders such as degenerative disk disease and sciatica. Theacronym “CNS” refers to disorders of the central nervous system, i.e.,brain and spinal cord.

The terms “ocular disease” or “ophthalmic disease,” as used herein,refer to diseases which affect the eye or eyes and potentially thesurrounding tissues as well. Ocular or ophthalmic diseases include, butare not limited to, conjunctivitis, retinitis, scleritis, uveitis,allergic conjunctivitis, vernal conjunctivitis, papillaryconjunctivitis.

The term “interstitial cystitis” refers to a disorder characterized bylower abdominal discomfort, frequent and sometimes painful urinationthat is not caused by anatomical abnormalities, infection, toxins,trauma or tumors.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of any of Formula (I), Formula (II), orFormula (III) and a co-agent, are both administered to a subjectsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that the active ingredients, e.g. acompound of any of Formula (I), Formula (II), or Formula (III) and aco-agent, are administered to a subject as separate entities eithersimultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the subject. The latter alsoapplies to cocktail therapy, e.g. the administration of three or moreactive ingredients.

The term “pharmaceutical composition” refers to a mixture of a compoundof any of Formula (I), Formula (II), or Formula (III) with otherchemical components, such as carriers, stabilizers, diluents, dispersingagents, suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. Multiple techniques of administering a compound exist inthe art including, but not limited to: intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary and topical administration.

The term “respiratory disease,” as used herein, refers to diseasesaffecting the organs that are involved in breathing, such as the nose,throat, larynx, Eustachian tubes, trachea, bronchi, lungs, relatedmuscles (e.g., diaphragm and intercostals) and nerves. Respiratorydiseases include, but are not limited to, asthma, adult respiratorydistress syndrome and allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allergen-induced asthma, neutrophilic asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, seasonal asthma,seasonal allergic rhinitis, perennial allergic rhinitis, chronicobstructive pulmonary disease, including chronic bronchitis oremphysema, pulmonary hypertension, interstitial lung fibrosis and/orairway inflammation and cystic fibrosis, and hypoxia.

The term “subject” or “subject” encompasses mammals, including but notlimited to, any member of the Mammalian class: humans, non-humanprimates such as chimpanzees, and other apes and monkey species; farmanimals such as cattle, horses, sheep, goats, swine; domestic animalssuch as rabbits, dogs, and cats; laboratory animals including rodents,such as rats, mice and guinea pigs, and the like. In one embodiment ofthe methods and compositions provided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

Pharmaceutical Composition/Formulation

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. In specific embodiments, pharmaceuticalcompositions are formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any pharmaceuticallyacceptable techniques, carriers, and excipients are used as suitable toformulate the pharmaceutical compositions described herein: Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound ofany of Formula (I), Formula (II), or Formula (III) and apharmaceutically acceptable diluent(s), excipient(s), or carrier(s). Incertain embodiments, the compounds described are administered aspharmaceutical compositions in which compounds of any of Formula (I),Formula (II), or Formula (III) are mixed with other active ingredients,as in combination therapy. Encompassed herein are all combinations ofactives set forth in the combination therapies section below andthroughout this disclosure. In specific embodiments, the pharmaceuticalcompositions include one or more compounds of any of Formula (I),Formula (II), or Formula (III).

A pharmaceutical composition, as used herein, refers to a mixture of acompound of any of Formula (I), Formula (II), or Formula (III) withother chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. In certain embodiments, the pharmaceutical compositionfacilitates administration of the compound to an organism. In someembodiments, practicing the methods of treatment or use provided herein,therapeutically effective amounts of compounds of any of Formula (I),Formula (II), or Formula (III) provided herein are administered in apharmaceutical composition to a mammal having a disease or condition tobe treated. In specific embodiments, the mammal is a human. In certainembodiments, therapeutically effective amounts vary depending on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. The compounds describedherein are used singly or in combination with one or more therapeuticagents as components of mixtures.

In one embodiment, one or more compounds of any of Formula (I), Formula(II), or Formula (III) is formulated in an aqueous solutions. Inspecific embodiments, the aqueous solution is selected from, by way ofexample only, a physiologically compatible buffer, such as Hank'ssolution, Ringer's solution, or physiological saline buffer. In otherembodiments, one or more compound of any of Formula (I), Formula (II),or Formula (III) is formulated for transmucosal administration. Inspecific embodiments, transmucosal formulations include mucoadhesiveagents that provide for association between the formulation and amucosal membrane, and/or penetrants that are appropriate to the barrierto be permeated. In still other embodiments wherein the compoundsdescribed herein are formulated for other parenteral injections,appropriate formulations include aqueous or nonaqueous solutions. Inspecific embodiments, such solutions include physiologically compatiblebuffers and/or excipients.

In another embodiment, compounds described herein are formulated fororal administration. Compounds described herein, including compounds ofany of Formula (I), Formula (II), or Formula (III) are formulated bycombining the active compounds with, e.g., pharmaceutically acceptablecarriers or excipients. In various embodiments, the compounds describedherein are formulated in oral dosage forms that include, by way ofexample only, tablets, powders, pills, dragees, capsules, liquids, gels,syrups, elixirs, slurries, suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as:for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose; orothers such as: polyvinylpyrrolidone (PVP or povidone) or calciumphosphate. In specific embodiments, disintegrating agents are optionallyadded. Disintegrating agents include, by way of example only,cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, oralginic acid or a salt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, therapeutically effective amounts of at leastone of the compounds described herein are formulated into other oraldosage forms. Oral dosage forms include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. In specific embodiments,push-fit capsules contain the active ingredients in admixture with oneor more filler. Fillers include, by way of example only, lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In other embodiments, softcapsules, contain one or more active compound that is dissolved orsuspended in a suitable liquid. Suitable liquids include, by way ofexample only, one or more fatty oil, liquid paraffin, or liquidpolyethylene glycol. In addition, stabilizers are optionally added.

In other embodiments, therapeutically effective amounts of at least oneof the compounds described herein are formulated for buccal orsublingual administration. Formulations suitable for buccal orsublingual administration include, by way of example only, tablets,lozenges, or gels.

In still other embodiments, the compounds described herein areformulated for parental injection, including formulations suitable forbolus injection or continuous infusion. In specific embodiments,formulations for injection are presented in unit dosage form (e.g., inampoules) or in multi-dose containers. Preservatives are, optionally,added to the injection formulations. In still other embodiments, thepharmaceutical composition of any of Formula (I), Formula (II), orFormula (III) are formulated in a form suitable for parenteral injectionas a sterile suspensions, solutions or emulsions in oily or aqueousvehicles. Parenteral injection formulations optionally containformulatory agents such as suspending, stabilizing and/or dispersingagents. In specific embodiments, pharmaceutical formulations forparenteral administration include aqueous solutions of the activecompounds in water-soluble form. In additional embodiments, suspensionsof the active compounds are prepared as appropriate oily injectionsuspensions. Suitable lipophilic solvents or vehicles for use in thepharmaceutical compositions described herein include, by way of exampleonly, fatty oils such as sesame oil, or synthetic fatty acid esters,such as ethyl oleate or triglycerides, or liposomes. In certain specificembodiments, aqueous injection suspensions contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension containssuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, in other embodiments, the active ingredient is in powderform for constitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

In one aspect, compounds of Formula (I), Formula (II), or Formula (III)are prepared as solutions for parenteral injection as described aboveand administered with an automatic injector. Automatic injectors, suchas those disclosed in U.S. Pat. Nos. 4,031,893, 5,358,489; 5,540,664;5,665,071, 5,695,472 and WO/2005/087297 (each of which are incorporatedherein by reference in its entirety) are known. In general, allautomatic injectors contain a volume of solution that includes acompound of Formula (I), Formula (II), or Formula (III) to be injected.In general, automatic injectors include a reservoir for holding thesolution, which is in fluid communication with a needle for deliveringthe drug, as well as a mechanism for automatically deploying the needle,inserting the needle into the patient and delivering the dose into thepatient. Exemplary injectors provide about 0.3 mL of solution at about aconcentration of 0.5 mg to 10 mg of compound of Formula (I), Formula(II), or Formula (III) per 1 mL of solution. Each injector is capable ofdelivering only one dose of the compound.

In still other embodiments, the compounds of any of Formula (I), Formula(II), or Formula (III) are administered topically. The compoundsdescribed herein are formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical compositions optionally contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

In yet other embodiments, the compounds of any of Formula (I), Formula(II), or Formula (III) are formulated for transdermal administration. Inspecific embodiments, transdermal formulations employ transdermaldelivery devices and transdermal delivery patches and can be lipophilicemulsions or buffered, aqueous solutions, dissolved and/or dispersed ina polymer or an adhesive. In various embodiments, such patches areconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents. In additional embodiments, the transdermaldelivery of the compounds of any of Formula (I), Formula (II), orFormula (III) is accomplished by means of iontophoretic patches and thelike. In certain embodiments, transdermal patches provide controlleddelivery of the compounds of any of Formula (I), Formula (II), orFormula (III). In specific embodiments, the rate of absorption is slowedby using rate-controlling membranes or by trapping the compound within apolymer matrix or gel. In alternative embodiments, absorption enhancersare used to increase absorption. Absorption enhancers or carriersinclude absorbable pharmaceutically acceptable solvents that assistpassage through the skin. For example, in one embodiment, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

In other embodiments, the compounds of any of Formula (I), Formula (II),or Formula (III) are formulated for administration by inhalation.Various forms suitable for administration by inhalation include, but arenot limited to, aerosols, mists or powders. Pharmaceutical compositionsof any of Formula (I), Formula (II), or Formula (III) are convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebuliser, with the use of a suitable propellant (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas). Inspecific embodiments, the dosage unit of a pressurized aerosol isdetermined by providing a valve to deliver a metered amount. In certainembodiments, capsules and cartridges of, such as, by way of exampleonly, gelatin for use in an inhaler or insufflator are formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

In still other embodiments, the compounds of any of Formula (I), Formula(II), or Formula (III) are formulated in rectal compositions such asenemas, rectal gels, rectal foams, rectal aerosols, suppositories, jellysuppositories, or retention enemas, containing conventional suppositorybases such as cocoa butter or other glycerides, as well as syntheticpolymers such as polyvinylpyrrolidone, PEG, and the like. In suppositoryforms of the compositions, a low-melting wax such as, but not limitedto, a mixture of fatty acid glycerides, optionally in combination withcocoa butter is first melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients is optionally used as suitable and asunderstood in the art. Pharmaceutical compositions comprising a compoundof any of Formula (I), Formula (II), or Formula (III) may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and at least one compound ofany of Formula (I), Formula (II), or Formula (III) described herein asan active ingredient. The active ingredient is in free-acid or free-baseform, or in a pharmaceutically acceptable salt form. In addition, themethods and pharmaceutical compositions described herein include the useof N-oxides, crystalline forms (also known as polymorphs), as well asactive metabolites of these compounds having the same type of activity.All tautomers of the compounds described herein are included within thescope of the compounds presented herein. Additionally, the compoundsdescribed herein encompass unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the compounds presented herein are alsoconsidered to be disclosed herein. In addition, the pharmaceuticalcompositions optionally include other medicinal or pharmaceuticalagents, carriers, adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure, buffers, and/or other therapeutically valuable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The form of the pharmaceuticalcompositions described herein include liquid solutions or suspensions,solid forms suitable for solution or suspension in a liquid prior touse, or as emulsions. These compositions also optionally contain minoramounts of nontoxic, auxiliary substances, such as wetting oremulsifying agents, pH buffering agents, and so forth.

In some embodiments, pharmaceutical composition comprising at least onecompound of any of Formula (I), Formula (II), or Formula (III)illustratively takes the form of a liquid where the agents are presentin solution, in suspension or both. Typically when the composition isadministered as a solution or suspension a first portion of the agent ispresent in solution and a second portion of the agent is present inparticulate form, in suspension in a liquid matrix. In some embodiments,a liquid composition includes a gel formulation. In other embodiments,the liquid composition is aqueous.

In certain embodiments, useful aqueous suspension contain one or morepolymers as suspending agents. Useful polymers include water-solublepolymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linkedcarboxyl-containing polymers. Certain pharmaceutical compositionsdescribed herein comprise a mucoadhesive polymer, selected for examplefrom carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Useful pharmaceutical compositions also, optionally, includesolubilizing agents to aid in the solubility of a compound of any ofFormula (I), Formula (II), or Formula (III). The term “solubilizingagent” generally includes agents that result in formation of a micellarsolution or a true solution of the agent. Certain acceptable nonionicsurfactants, for example Polysorbate 80, are useful as solubilizingagents, as can ophthalmically acceptable glycols, polyglycols, e.g.,polyethylene glycol 400, and glycol ethers.

Furthermore, useful pharmaceutical compositions optionally include oneor more pH adjusting agents or buffering agents, including acids such asacetic, boric, citric, lactic, phosphoric and hydrochloric acids; basessuch as sodium hydroxide, sodium phosphate, sodium borate, sodiumcitrate, sodium acetate, sodium lactate andtris-hydroxymethylaminomethane; and buffers such as citrate/dextrose,sodium bicarbonate and ammonium chloride. Such acids, bases and buffersare included in an amount required to maintain pH of the composition inan acceptable range.

Additionally, useful compositions also, optionally, include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other useful pharmaceutical compositions optionally include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

Still other useful compositions include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other useful compositions may include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. Alternatively, multiple-dosereclosable containers are used, in which case it is typical to include apreservative in the composition.

In alternative embodiments, other delivery systems for hydrophobicpharmaceutical compounds are employed. Liposomes and emulsions areexamples of delivery vehicles or carriers useful herein. In certainembodiments, organic solvents such as N-methylpyrrolidone are alsoemployed. In additional embodiments, the compounds described herein aredelivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials are useful herein. In someembodiments, sustained-release capsules release the compounds for a fewweeks up to over 100 days. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization may be employed.

In certain embodiments, the formulations described herein comprise oneor more antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

Methods of Dosing and Treatment Regimens

In one embodiment, the compound of any of Formula (I), Formula (II), orFormula (III) are used in the preparation of medicaments for thetreatment of PGD₂-dependent or PGD₂-mediated diseases or conditions. Inaddition, a method for treating any of the diseases or conditionsdescribed herein in a subject in need of such treatment, involvesadministration of pharmaceutical compositions containing at least onecompound of any of Formula (I), Formula (II), or Formula (III) or apharmaceutically acceptable salt, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, in therapeutically effective amounts to said subject.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a subject already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest thesymptoms of the disease or condition. Amounts effective for this usedepend on the severity and course of the disease or condition, previoustherapy, the subject's health status, weight, and response to the drugs,and the judgment of the treating physician. Therapeutically effectiveamounts are optionally determined by methods including, but not limitedto, a dose escalation clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a subject susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the subject'sstate of health, weight, and the like. When used in a subject, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the subject's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In certain embodiments wherein the subject's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the subject's life in order toameliorate or otherwise control or limit the symptoms of the subject'sdisease or condition.

In certain embodiments wherein a subject's status does improve,administration of the compounds is given continuously; or,alternatively, the dose of drug being administered may be temporarilyreduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”). In specific embodiments, the length of the drug holidayis between 2 days and 1 year, including by way of example only, 2 days,3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days,and 365 days. The dose reduction during a drug holiday is, by way ofexample only, by 10%-100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the subject's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the subject requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

In some embodiments, compounds of Formula (I), (II) or (III) areadministered chronically. In some embodiments, compounds of Formula (I),(II) or (III) are administered intermittently (e.g. drug holiday thatincludes a period of time in which the compound is not administered oris administered in a reduced amount). In some embodiments, compounds ofFormula (I), (II) or (III) are administered in cycles that include: (a)a first period that includes daily administration of the compound ofFormula (I), (II) or (III); followed by (b) a second period thatincludes a dose reduction of the daily amount of compound of Formula(I), (II) or (III) that is administered. In some embodiments, thecompound of Formula (I), (II) or (III) is not administered in the secondperiod. In some embodiments, the duration of the first and secondperiods, as well as the dose amounts are determined using methodsdescribed herein or known in the art.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated. In general, however, doses employed for adult humantreatment are typically in the range of 0.02-5000 mg per day, preferably1-1500 mg per day. In one embodiment, the desired dose is convenientlypresented in a single dose or in divided doses administeredsimultaneously (or over a short period of time) or at appropriateintervals, for example as two, three, four or more sub-doses per day.

In certain embodiments, the pharmaceutical composition described hereinis in unit dosage forms suitable for single administration of precisedosages. In unit dosage form, the formulation is divided into unit dosescontaining appropriate quantities of one or more compound. In specificembodiments, the unit dosage is in the form of a package containingdiscrete quantities of the formulation. Non-limiting examples arepackaged tablets or capsules, and powders in vials or ampoules. Aqueoussuspension compositions are optionally packaged in single-dosenon-re-closeable containers. Alternatively, multiple-dose re-closeablecontainers are used, in which case it is typical to include apreservative in the composition. By way of example only, formulationsfor parenteral injection are, in some embodiments, presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

In one embodiment, the daily dosages appropriate for the compound of anyof Formula (I), Formula (II), or Formula (III) described herein are fromabout 0.01 to about 10 mg/kg per body weight. In specific embodiments,an indicated daily dosage in a large mammal, including, but not limitedto, humans, is in the range from about 0.5 mg to about 1000 mg,conveniently administered in divided doses, including, but not limitedto, up to four times a day or in extended release form. In certainembodiments, suitable unit dosage forms for oral administration comprisefrom about 1 to 500 mg active ingredient. In other embodiments, thedaily dosage or the amount of active in the dosage form are lower orhigher than the ranges indicated herein, based on a number of variablesin regard to an individual treatment regime. In various embodiments, thedaily and unit dosages are altered depending on a number of variablesincluding, but not limited to, the activity of the compound used, thedisease or condition to be treated, the mode of administration, therequirements of the individual subject, the severity of the disease orcondition being treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit is expressed as the ratio between LD₅₀ and ED₅₀. In certainembodiments, the data obtained from cell culture assays and animalstudies are used in formulating the therapeutically effective dailydosage range and/or the therapeutically effective unit dosage amount foruse in mammals, including humans. In some embodiments, the daily dosageamount of the compounds described herein lies within a range ofcirculating concentrations that include the ED₅₀ with minimal toxicity.In certain embodiments, the daily dosage range and/or the unit dosageamount varies within this range depending upon the dosage form employedand the route of administration utilized.

The therapy of PGD₂-dependent or PGD₂-mediated diseases or conditions isdesigned to modulate the activity of DP₂, DP₁ and/or TP. Such modulationincludes, in some embodiments, antagonizing DP₂ activity. In otherembodiments, such modulation includes antagonizing DP₂ and DP₁. Forexample, in one embodiment, a DP₂ antgonist is administered in order todecrease signal transduction initiated by PGD₂ within the individual.

In accordance with one aspect, compositions and methods described hereininclude compositions and methods for treating, preventing, reversing,halting or slowing the progression of PGD₂-dependent or PGD₂ mediateddiseases or conditions once it becomes clinically evident, or treatingthe symptoms associated with or related to PGD₂-dependent or PGD₂mediated diseases or conditions, by administering to the subject acompound of any of Formula (I), Formula (II), or Formula (III) orpharmaceutical composition or medicament which includes a compound ofany of Formula (I), Formula (II), or Formula (III). In certainembodiments, the subject already has a PGD₂-dependent or PGD₂ mediateddisease or condition at the time of administration, or is at risk ofdeveloping a PGD₂-dependent or PGD₂ mediated disease or condition.

In certain aspects, the activity of DP₂ in a mammal is directly orindirectly modulated by the administration of (at least once) aneffective amount of at least one compound of any of Formula (I), Formula(II), or Formula (III) or pharmaceutical composition or medicament whichincludes a compound of any of Formula (I), Formula (II), or Formula(III) to a mammal. Such modulation includes, but is not limited to,reducing and/or inhibiting the activity of DP₂. In additional aspects,the activity of PGD₂ in a mammal is directly or indirectly modulated,including reducing and/or inhibiting, by the administration of (at leastonce) an effective amount of at least one compound of any of Formula(I), Formula (II), or Formula (III) or pharmaceutical composition ormedicament which includes a compound of any of Formula (I), Formula(II), or Formula (III) to a mammal. Such modulation includes, but is notlimited to, reducing and/or inhibiting the activity of DP₂.

In one embodiment, prevention and/or treatment of PGD₂-dependent or PGD₂mediated diseases or conditions comprises administering to a mammal atleast once a therapeutically effective amount of at least one compoundof any of Formula (I), Formula (II), or Formula (III) or pharmaceuticalcomposition or medicament which includes a compound of any of Formula(I), Formula (II), or Formula (III). In specific embodiments, thecompound administered to the mammal is a compound of any of Formula (I),Formula (II), or Formula (III). In some embodiments, there is provided amethod of treating PGD₂-dependent or PGD₂ mediated diseases orconditions that include, but are not limited to, bone diseases anddisorders, cardiovascular diseases and disorders, inflammatory diseasesand disorders, immunological diseases or disorders, dermatologicaldiseases and disorders, ocular diseases and disorders, cancer and otherproliferative diseases and disorders, respiratory diseases and disorder,and non-cancerous disorders.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound of any of Formula (I), Formula (II), or Formula(III) or pharmaceutical composition or medicament which includes acompound of any of Formula (I), Formula (II), or Formula (III). By wayof example, in some embodiments, the respiratory disease is asthma.Other respiratory diseases include, but are not limited to, adultrespiratory distress syndrome and allergic (extrinsic) asthma,non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma,clinical asthma, nocturnal asthma, allergen-induced asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, seasonal asthma,allergic rhinitis, vascular responses, endotoxin shock, fibrogenesis,pulmonary fibrosis, allergic diseases, chronic inflammation, and adultrespiratory distress syndrome.

By way of example only, included in such treatment methods are methodsfor preventing chronic obstructive pulmonary disease comprisingadministering to the mammal at least once an effective amount of atleast one compound of any of Formula (I), Formula (II), or Formula (III)or pharmaceutical composition or medicament which includes a compound ofany of Formula (I), Formula (II), or Formula (III). In addition, chronicobstructive pulmonary disease includes, but is not limited to, chronicbronchitis or emphysema, pulmonary hypertension, interstitial lungfibrosis and/or airway inflammation and cystic fibrosis.

By way of example only, included in such treatment methods are methodsfor preventing increased mucosal secretion and/or edema in a disease orcondition comprising administering to the mammal at least once aneffective amount of at least one compound of any of Formula (I), Formula(II), or Formula (III) or pharmaceutical composition or medicament whichincludes a compound of any of Formula (I), Formula (II), or Formula(III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or treatingvasoconstriction, atherosclerosis and its sequelae myocardial ischemia,myocardial infarction, aortic aneurysm, vasculitis and stroke comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (I), Formula (II), or Formula (III)or pharmaceutical composition or medicament which includes a compound ofany of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for reducing cardiac reperfusion injuryfollowing myocardial ischemia and/or endotoxic shock comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (I), Formula (II), or Formula (III)or pharmaceutical composition or medicament which includes a compound ofany of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for reducing the constriction of bloodvessels in a mammal comprising administering at least once to the mammalan effective amount of at least one compound of any of Formula (I),Formula (II), or Formula (III) or pharmaceutical composition ormedicament which includes a compound of any of Formula (I), Formula(II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for lowering or preventing an increase inblood pressure of a mammal comprising administering at least once to themammal an effective amount of at least one compound of any of Formula(I), Formula (II), or Formula (III) or pharmaceutical composition ormedicament which includes a compound of any of Formula (I), Formula(II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or treating eosinophiland/or basophil and/or dendritic cell and/or neutrophil and/or monocyteand/or T-cell recruitment comprising administering at least once to themammal an effective amount of at least one compound of any of Formula(I), Formula (II), or Formula (III) or pharmaceutical composition ormedicament which includes a compound of any of Formula (I), Formula(II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the prevention or treatment of abnormalbone remodeling, loss or gain, including diseases or conditions as, byway of example, osteopenia, osteoporosis, Paget's disease, cancer andother diseases comprising administering at least once to the mammal aneffective amount of at least one compound of any of Formula (I), Formula(II), or Formula (III) or pharmaceutical composition or medicament whichincludes a compound of any of Formula (I), Formula (II), or Formula(III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing ocular inflammation andallergic conjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis comprising administering at least once to the mammal aneffective amount of at least one compound of any of Formula (I), Formula(II), or Formula (III) or pharmaceutical composition or medicament whichincludes a compound of any of Formula (I), Formula (II), or Formula(III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing otitis, otitis mediacomprising administering at least once to the mammal an effective amountof at least one compound of any of Formula (I), Formula (II), or Formula(III) or pharmaceutical composition or medicament which includes acompound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing CNS disorders comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (I), Formula (II), or Formula (III)or pharmaceutical composition or medicament which includes a compound ofany of Formula (I), Formula (II), or Formula (III). CNS disordersinclude, but are not limited to, multiple sclerosis, Parkinson'sdisease, Alzheimer's disease, stroke, cerebral ischemia, retinalischemia, post-surgical cognitive dysfunction, migraine, peripheralneuropathy/neuropathic pain, spinal cord injury, cerebral edema and headinjury.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of cancer comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (I), Formula (II), or Formula(III), or pharmaceutical composition or medicament which includes acompound of any of Formula (I), Formula (II), or Formula (III). The typeof cancer may include, but is not limited to, pancreatic cancer andother solid or hematological tumors.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or reducing the chances ofendotoxic shock and septic shock comprising administering at least onceto the mammal an effective amount of at least one compound of any ofFormula (I), Formula (II), or Formula (III) or pharmaceuticalcomposition or medicament which includes a compound of any of Formula(I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein methods for preventing, treating or alleviatingrheumatoid arthritis and osteoarthritis comprising administering atleast once to the mammal an effective amount of at least one compound ofany of Formula (I), Formula (II), or Formula (III) or pharmaceuticalcomposition or medicament which includes a compound of any of Formula(I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing increased, reducing theincidences of or treating gastrointestinal diseases comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (I), Formula (II), or Formula (III)or pharmaceutical composition or medicament which includes a compound ofany of Formula (I), Formula (II), or Formula (III). Suchgastrointestinal diseases include, by way of example only, inflammatorybowel disease (IBD), colitis and Crohn's disease.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the reduction or treatment ofinflammation and/or preventing, reducing the incidences of or treatingacute or chronic transplant rejection (including any vascularabnormality associated with acute or chronic rejection) or preventing ortreating tumors or accelerating the healing of wounds comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (I), Formula (II), or Formula (III)or pharmaceutical composition or medicament which includes a compound ofany of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the prevention or treatment ofrejection or dysfunction in a transplanted organ or tissue comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (I), Formula (II), or Formula (III)or pharmaceutical composition or medicament which includes a compound ofany of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating type II diabetes comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (I), Formula (II), or Formula (III)or pharmaceutical composition or medicament which includes a compound ofany of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating inflammatory responses of theskin comprising administering at least once to the mammal an effectiveamount of at least one compound of any of Formula (I), Formula (II), orFormula (III) or pharmaceutical composition or medicament which includesa compound of any of Formula (I), Formula (II), or Formula (III). Suchinflammatory responses of the skin include, by way of example,psoriasis, dermatitis, contact dermatitis, eczema, urticaria, rosacea,wound healing and scarring. In another aspect are methods for reducingpsoriatic lesions in the skin, joints, or other tissues or organs,comprising administering at least once to the mammal an effective amountof at least one compound of any of Formula (I), Formula (II), or Formula(III) or pharmaceutical composition or medicament which includes acompound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of cystitis, including,e.g., interstitial cystitis, comprising administering at least once tothe mammal an effective amount of at least one compound of any ofFormula (I), Formula (II), or Formula (III) or pharmaceuticalcomposition or medicament which includes a compound of any of Formula(I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of metabolic syndromessuch as Familial Mediterranean Fever comprising administering at leastonce to the mammal an effective amount of at least one compound of anyof Formula (I), Formula (II), or Formula (III) or pharmaceuticalcomposition or medicament which includes a compound of any of Formula(I), Formula (II), or Formula (III).

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound of any of Formula (I), Formula (II), or Formula (III) incombination with another therapeutic agent. By way of example only, ifone of the side effects experienced by a subject upon receiving one ofthe compounds herein is inflammation, then it may be appropriate toadminister an anti-inflammatory agent in combination with the initialtherapeutic agent. Or, in one embodiment, the therapeutic effectivenessof one of the compounds described herein is enhanced by administrationof an adjuvant (i.e., by itself the adjuvant may have minimaltherapeutic benefit, but in combination with another therapeutic agent,the overall therapeutic benefit to the subject is enhanced). Or, in someembodiments, the benefit of experienced by a subject is increased byadministering one of the compounds described herein with anothertherapeutic agent (which also includes a therapeutic regimen) that alsohas therapeutic benefit. In one specific embodiment, the therapeuticbenefit of treating asthma by administering at least one of thecompounds described herein is increased by also providing the subjectwith other therapeutic agents or therapies for asthma. In any case,regardless of the disease, disorder or condition being treated, theoverall benefit experienced by the subject may simply be additive of thetwo therapeutic agents or the subject may experience a synergisticbenefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulatingpharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with one ormore additional agent, such as an additional therapeutically effectivedrug, an adjuvant or the like. Therapeutically-effective dosages ofdrugs and other agents for use in combination treatment regimens can bedetermined by means similar to those set forth hereinabove for theactives themselves. Furthermore, the methods of prevention/treatmentdescribed herein encompasses the use of metronomic dosing, i.e.,providing more frequent, lower doses in order to minimize toxic sideeffects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a DP₂antagonist described herein is initiated prior to, during, or aftertreatment with a second agent described above, and continues until anytime during treatment with the second agent or after termination oftreatment with the second agent. It also includes treatments in which aDP₂ antagonist described herein and the second agent being used incombination are administered simultaneously or at different times and/orat decreasing or increasing intervals during the treatment period.Combination treatment further includes periodic treatments that startand stop at various times to assist with the clinical management of thesubject. For example, in one embodiment, a DP₂ antagonist describedherein in the combination treatment is administered weekly at the onsetof treatment, decreasing to biweekly, and decreasing further asappropriate.

Compositions and methods for combination therapy are provided herein. Inaccordance with one aspect, the pharmaceutical compositions disclosedherein are used to treat PGD₂-dependent or PGD₂ mediated conditions. Inaccordance with another aspect, the pharmaceutical compositionsdisclosed herein are used to treat respiratory diseases (e.g., asthma),where treatment with a DP₂ antagonist is indicated and to inducebronchodilation in a subject. In one embodiment, the pharmaceuticalcompositions disclosed herein are used to treat airways or nasalinflammation diseases such as asthma and rhinitis.

In one embodiment, pharmaceutical compositions disclosed herein are usedto treat a subject suffering from a vascular inflammation-drivendisorder. In one embodiment, the pharmaceutical compositions disclosedherein are used to treat skin inflammation diseases such as atopicdermatitis.

In certain embodiments, combination therapies described herein are usedas part of a specific treatment regimen intended to provide a beneficialeffect from the co-action of a DP₂ described herein and a concurrenttreatment. It is understood that the dosage regimen to treat, prevent,or ameliorate the condition(s) for which relief is sought, is modifiedin accordance with a variety of factors. These factors include the typeof respiratory disorder and the type of bronchoconstriction orinflammation from which the subject suffers, as well as the age, weight,sex, diet, and medical condition of the subject. Thus, in someinstances, the dosage regimen actually employed varies and, in someembodiments, deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more biologically active agents, thecompound provided herein is administered either simultaneously with thebiologically active agent(s), or sequentially. If administeredsequentially, the attending physician decides on the appropriatesequence of administering protein in combination with the biologicallyactive agent(s).

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills). In one embodiment, one of the therapeutic agents isgiven in multiple doses, and in another, two (or more if present) aregiven as multiple doses. In some embodiments of non-simultaneousadministration, the timing between the multiple doses vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations is alsoenvisioned.

In additional embodiments, the compounds of any of Formula (I), Formula(II), or Formula (III) are used in combination with procedures thatprovide additional or synergistic benefit to the subject. By way ofexample only, subjects are expected to find therapeutic and/orprophylactic benefit in the methods described herein, whereinpharmaceutical composition of any of Formula (I), Formula (II), orFormula (III) and/or combinations with other therapeutics are combinedwith genetic testing to determine whether that individual is a carrierof a mutant gene that is known to be correlated with certain diseases orconditions.

The compounds of any of Formula (I), Formula (II), or Formula (III) andcombination therapies are administered before, during or after theoccurrence of a disease or condition, and the timing of administeringthe composition containing a compound varies. Thus, in one embodiment,the compounds described herein are used as a prophylactic and areadministered continuously to subjects with a propensity to developconditions or diseases in order to prevent the occurrence of the diseaseor condition. In another embodiment, the compounds and compositions areadministered to a subject during or as soon as possible after the onsetof the symptoms. The administration of the compounds are initiatedwithin the first 48 hours of the onset of the symptoms, preferablywithin the first 48 hours of the onset of the symptoms, more preferablywithin the first 6 hours of the onset of the symptoms, and mostpreferably within 3 hours of the onset of the symptoms. The initialadministration is accomplished via any practical route, such as, forexample, by intravenous injection, a bolus injection, infusion over 5minutes to about 5 hours, a pill, a capsule, transdermal patch, buccaldelivery, and the like, or combination thereof. In specific embodiments,a compound described herein is administered as soon as is practicableafter the onset of a disease or condition is detected or suspected, andfor a length of time necessary for the treatment of the disease, suchas, for example, from about 1 month to about 3 months. In someembodiments, the length required for effective treatment varies, and thetreatment length is adjusted to suit the specific needs of each subject.For example, in specific embodiments, a compound described herein or aformulation containing the compound is administered for at least 2weeks, about 1 month to about 5 years, or from about 1 month to about 3years.

By way of example, therapies which combine compounds of any of Formula(I), Formula (II), or Formula (III) with inhibitors of PGD₂ synthesis orPGD₂ receptor antagonists, either acting at the same or other points inthe PGD₂ synthesis pathway, are encompassed herein for treatingPGD₂-dependent or PGD₂ mediated diseases or conditions. In addition, byway of example, encompassed herein are therapies that combine compoundsof any of Formula (I), Formula (II), or Formula (III) with inhibitors ofinflammation for treating PGD₂-dependent or PGD₂ mediated diseases orconditions.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includeadministration to a subject compounds, pharmaceutical compositions, ormedicaments described herein in combination with an anti-inflammatoryagent including, but not limited to, non-steroidal anti-inflammatorydrugs (NSAIDs) and corticosteroids (glucocorticoids). Anti-inflammatoryagents include, but are not limited to: arthrotec, mesalamine,auralglan, sulfasalazine, daypro, etodolac, ponstan, and solumedrol;non-steroidal anti-inflammatory agents; corticosteroids; and leukotrienepathway modulators (e.g. montelukast, zilueton).

By way of example only, asthma is a chronic inflammatory diseasecharacterized by pulmonary eosinophilia and airway hyperresponsiveness.In subjects with asthma, PGD₂ is released from mast cells, eosinophils,and basophils. PGD₂ is involved in contraction of airway smooth muscle,an increase in vascular permeability and mucus secretions, and has beenreported to attract and activate inflammatory cells in the airways ofasthmatics. Thus, in another embodiment described herein, the methodsfor treatment of respiratory diseases include administration to asubject compounds, pharmaceutical compositions, or medicaments describedherein in combination with an anti-inflammatory agent.

NSAIDs include, but are not limited to: aspirin, salicylic acid,gentisic acid, choline magnesium salicylate, choline salicylate, cholinemagnesium salicylate, choline salicylate, magnesium salicylate, sodiumsalicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium,flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolactromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin,sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid,piroxicam, meloxicam, COX-2 specific inhibitors (such as, but notlimited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,lumiracoxib, CS-502, JTE-522, L-745,337 and NS398).

Corticosteroids, include, but are not limited to: betamethasone(Celestone), prednisone (Deltasone), alclometasone, aldosterone,amcinonide, beclometasone, betamethasone, budesonide, ciclesonide,clobetasol, clobetasone, clocortolone, cloprednol, cortisone,cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone,desoxycortone, dexamethasone, diflorasone, diflucortolone,difluprednate, fluclorolone, fludrocortisone, fludroxycortide,flumetasone, flunisolide, fluocinolone acetonide, fluocinonide,fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene,fluticasone, formocortal, halcinonide, halometasone,hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone butyrate, loteprednol, medrysone,meprednisone, methylprednisolone, methylprednisolone aceponate,mometasone furoate, paramethasone, prednicarbate,prednisone/prednisolone, rimexolone, tixocortol, triamcinolone, andulobetasol.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includeadministration to a subject compounds, pharmaceutical compositions, ormedicaments described herein in combination in combination with NSAIDsand NO-donors or NSAIDs and proton-pump inhibitors.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includesadministering to a subject compounds, pharmaceutical compositions, ormedicaments described herein in combination with other PGD₂ receptorantagonists including, but are not limited to, DP₁ receptor antagonistsand TP receptor antagonists. In another embodiment described herein,methods for treatment of PGD₂-dependent or PGD₂ mediated conditions ordiseases includes administered to a subject compounds, pharmaceuticalcompositions, or medicaments described herein in combination with a DP₁receptor antagonist. DP₁ receptor antagonists include, but are notlimited to, BWA868C (Sharif et al., Br. J. Pharmacol., 2000 November;131(6): 1025-38), MK-0524 (Sturino et al, J. Med. Chem., 2007, 50,794-806 and Cheng et al, PNAS, 2006 Apr. 25; 103(17):6682-7.) and S-5751(Arimura et al., J. Pharmacol. Exp. Ther., 2001 August; 298(2):411-9).For some subjects, the most appropriate formulation or method of use ofsuch combination treatments depends on the type of PGD₂-dependent orPGD₂ mediated disorder, the time period in which the DP₂ antagonist actsto treat the disorder and/or the time period in which the DP₁ receptorantagonist acts to prevent DP₁ receptor activity. By way of exampleonly, some embodiments described herein provide for such combinationtreatments that are used for treating a subject suffering fromrespiratory disorders such as asthma and rhinitis.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includesadministering to a subject compounds, pharmaceutical compositions, ormedicaments described herein in combination with a TP receptorantagonist. TP receptor antagonists include, but are not limited to,Ramatroban (“Bayer™”), GR32191 (Beasley et al., J. Appl. Physiol., 1989April; 66(4):1685-93), ICH92605 (Boersma et al., Br. J. Pharmacal., 1999December; 128(7):1505-12) and derivatives or analogs thereof. Suchcombinations may be used to treat PGD₂-dependent or PGD₂ mediateddisorders, including respiratory disorders.

In one embodiment, the co-administration of a DP₂ receptor antagonistwith a DP₁ receptor antagonist or a TP receptor antagonist hastherapeutic benefit over and above the benefit derived from theadministration of a either a DP₂ antagonist, DP₁ antagonist or a TPantagonist alone. In the case that substantial inhibition of PGD₂activity has undesired effects, partial inhibition of this pathwaythrough the amelioration of the effects of the proinflammatory agonistscombined with the block of the DP₁ receptor, TP receptor and/or DP₂receptor may afford substantial therapeutic benefits, particularly forrespiratory diseases.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such asproliferative disorders, including cancer, comprises administration to asubject compounds, pharmaceutical compositions, or medicaments describedherein in combination with at least one additional agent selected, byway of example only, alemtuzumab, arsenic trioxide, asparaginase(pegylated or non-), bevacizumab, cetuximab, platinum-based compoundssuch as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin,irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate,Paclitaxel™, taxol, temozolomide, thioguanine, or classes of drugsincluding hormones (an antiestrogen, an antiandrogen, or gonadotropinreleasing hormone analogues, interferons such as alpha interferon,nitrogen mustards such as busulfan or melphalan or mechlorethamine,retinoids such as tretinoin, topoisomerase inhibitors such as irinotecanor topotecan, tyrosine kinase inhibitors such as gefinitinib orimatinib, or agents to treat signs or symptoms induced by such therapyincluding allopurinol, filgrastim, granisetron/ondansetron/palonosetron,dronabinol.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of transplanted organs or tissues or cells, comprisesadministration to a subject compounds, pharmaceutical compositions, ormedicaments described herein in combination with at least one additionalagent selected from, by way of example only, azathioprine, acorticosteroid, cyclophosphamide, cyclosporin, dacluzimab, mycophenolatemofetil, OKT3, rapamycin, tacrolimus, thymoglobulin.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such asatherosclerosis, comprises administration to a subject compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected, by way ofexample only, HMG-CoA reductase inhibitors (e.g., statins in theirlactonized or dihydroxy open acid forms and pharmaceutically acceptablesalts and esters thereof, including but not limited to lovastatin;simvastatin; dihydroxy open-acid simvastatin, particularly the ammoniumor calcium salts thereof; pravastatin, particularly the sodium saltthereof; fluvastatin, particularly the sodium salt thereof;atorvastatin, particularly the calcium salt thereof; nisvastatin, alsoreferred to as NK-104; rosuvastatin); agents that have bothlipid-altering effects and other pharmaceutical activities; HMG-CoAsynthase inhibitors; cholesterol absorption inhibitors such asezetimibe; cholesterol ester transfer protein (CETP) inhibitors, forexample JTT-705 and CP529, 414; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors);acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MTP)inhibitors; probucol; niacin; bile acid sequestrants; LDL (low densitylipoprotein) receptor inducers; platelet aggregation inhibitors, forexample glycoprotein IIb/IIIa fibrinogen receptor antagonists andaspirin; human peroxisome proliferator activated receptor gamma (PPARγ)agonists, including the compounds commonly referred to as glitazones,for example troglitazone, pioglitazone and rosiglitazone and includingthose compounds included within the structural class known asthiazolidinediones as well as those PPARγ agonists outside thethiazolidinedione structural class; PPARαagonists such as clofibrate,fenofibrate including micronized fenofibrate, and gemfibrozil; PPAR dualα/γ agonists such as 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide,known as KRP-297; vitamin B6 (also known as pyridoxine) and thepharmaceutically acceptable salts thereof such as the HCI salt; vitaminB12 (also known as cyanocobalamin); folic acid or a pharmaceuticallyacceptable salt or ester thereof such as the sodium salt and themethylglucamine salt; anti-oxidant vitamins such as vitamin C and E andbeta carotene; beta-blockers; angiotensin II antagonists such aslosartan; angiotensin converting enzyme inhibitors such as enalapril andcaptopril; calcium channel blockers such as nifedipine and diltiazam;endothelian antagonists; agents that enhance ABC1 gene expression; FXRand LXR ligands including both inhibitors and agonists; bisphosphonatecompounds such as alendronate sodium; and cyclooxygenase-2 inhibitorssuch as rofecoxib and celecoxib.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of stroke, comprises administration to a subject compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected from, by way ofexample only, COX-2 inhibitors; nitric oxide synthase inhibitors, suchas N-(3-(aminomethyl)benzyl)acetamidine; Rho kinase inhibitors, such asfasudil; angiotension II type-1 receptor antagonists, includingcandesartan, losartan, irbesartan, eprosartan, telmisartan andvalsartan; glycogen synthase kinase 3 inhibitors; sodium or calciumchannel blockers, including crobenetine; p38 MAP kinase inhibitors,including SKB 239063; thromboxane AX-synthetase inhibitors, includingisbogrel, ozagrel, ridogrel and dazoxiben; statins (HMG CoA reductaseinhibitors), including lovastatin, simvastatin, dihydroxy open-acidsimvastatin, pravastatin, fluvastatin, atorvastatin, nisvastatin, androsuvastatin; neuroprotectants, including free radical scavengers,calcium channel blockers, excitatory amino acid antagonists, growthfactors, antioxidants, such as edaravone, vitamin C, TROLOX™, citicolineand minicycline, and reactive astrocyte inhibitors, such as(2R)-2-propyloctanoic acid; beta andrenergic blockers, such aspropranolol, nadolol, timolol, pindolol, labetalol, metoprolol,atenolol, esmolol and acebutolol; NMDA receptor antagonists, includingmemantine; NR2B antagonists, such as traxoprodil; 5-HT1A agonists;receptor platelet fibrinogen receptor antagonists, including tirofibanand lamifiban; thrombin inhibitors; antithrombotics, such as argatroban;antihypertensive agents, such as enalapril; vasodilators, such ascyclandelate; nociceptin antagonists; DPN antagonists; CETP inhibitors;GABA 5 inverse agonists; and selective androgen receptor modulators.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of pulmonary fibrosis, comprises administration to a subjectcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from, by wayof example only, anti-inflammatory agents, such as corticosteroids,azathioprine or cyclophosphamide.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of interstitial cystitis, comprises administration to a subjectcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from, by wayof example only, dimethylsulfoxide, omalizumab, and pentosanpolysulfate.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of disorders of bone, comprises administration to a subjectcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from the, byway of example only, minerals, vitamins, bisphosphonates, anabolicsteroids, parathyroid hormone or analogs, and cathepsin K inhibitors.

In yet another embodiment described herein, methods for treatingPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of respiratory disorders (e.g., asthma, COPD and rhinitis),comprises administration to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with atleast one respiratory agent. Respiratory agents include, but are notlimited to, bronchodilators (e.g., sympathomimetic agents and xanthinederivatives), leukotriene receptor antagonists, leukotriene formationinhibitors, leukotriene modulators, nasal decongestants, respiratoryenzymes, lung surfactants, antihistamines (e.g., Mepyramine(pyrilamine), Antazoline, Diphenhydramine, Carbinoxamine, Doxylamine,Clemastine, Dimenhydrinate, Pheniramine, Chlorphenamine(chlorpheniramine), Dexchlorpheniramine, Brompheniramine, Triprolidine,cetirizine, Cyclizine, Chlorcyclizine, Hydroxyzine, Meclizine,loratadine, desloratidine, Promethazine, Alimemazine (trimeprazine),Cyproheptadine, Azatadine, Ketotifen, Acrivastine, Astemizole,Cetirizine, Mizolastine, Terfenadine, Azelastine, Levocabastine,Olopatadine, Levocetirizine, Fexofenadine), mucolytics, corticosteroids,glucocorticoids, anticholinergics, antitussives, analgesics,expectorants, albuterol, ephedrine, epinephrine, fomoterol,metaproterenol, terbutaline, budesonide, ciclesonide, dexamethasone,flunisolide, fluticasone propionate, triamcinolone acetonide,ipratropium bromide, pseudoephedrine, theophylline, montelukast,zafirlukast, pranlukast, tomelukast, ambrisentan, bosentan, enrasentan,sitaxsentan, tezosentan, iloprost, treprostinil, pirfenidone, FLAPinhibitors, FLAP modulators, 5-LO inhibitors, BLT1 receptor antagonistsand BLT2 receptor antagonists.

In a specific embodiment described herein, methods for treatingPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of asthma and/or COPD, comprises administration to a patientanti-inflammatory agents. In certain embodiments, methods for treatingPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of asthma and/or COPD, comprise administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from, but notlimited to, epinephrine, isoproterenol, orciprenaline, bronchodilators,glucocorticoids, leukotriene modifiers, mast-cell stabilizers,xanthines, anticholinergics, β-2 agonists, FLAP inhibitors, FLAPmodulators or 5-LO inhibitors. β-2 agonists include, but are not limitedto, short-acting β-2 agonists (e.g., salbutamol (albuterol),levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol,fenoterol and bitolterol mesylate) and long-acting β-2 agonists (e.g.,salmeterol, formoterol, bambuterol and clenbuterol). FLAP inhibitorsand/or FLAP modulators include, but are not limited to,3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid,3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid, MK-886, MK-0591, DG-031 (BAY-x1005) and compounds found in US2007/0225285, US 2007/0219206, US 2007/0173508, US 2007/0123522 and US2007/0105866 (each of which are hereby incorporated by reference).Glucocorticoids include, but are not limited to, beclometasone,budesonide, ciclesonide, fluticasone and mometasone. Anticholinergicsinclude, but are not limited to, ipratropium and tiotropium. Mast cellstabilizers include, but are not limited to, cromoglicate andnedocromil. Xanthines include, but are not limited to, amminophylline,theobromine and theophylline. Leukotriene antagonists include, but arenot limited to, montelukast, tomelukast, pranlukast and zafirlukast.5-LO inhibitors include, but are not limited to, zileuton, VIA-2291(ABT761), MK-0633, CJ-13,610 (PF-4191834), AZ-4407 and ZD-2138 andcompounds found in US 2007/0149579, WO2007/016784.

In another specific embodiment described herein, methods for treatingPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of rhinitis, comprises administration to a subject compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected from, by way ofexample only, antihistamines, leukotriene antagonists, corticosteroidsand decongestants. Leukotriene antagonists include, but are not limitedto, montelukast, tomelukast, pranlukast and zafirlukast.

In another aspect, methods for treating PGD₂-dependent or PGD₂ mediatedconditions or diseases, iclude administering a DP₂ antagonist describedherein in combination with other agents to treat respiratory diseases orconditions. Therapeutic agents used in the treatment of respiratoryconditions and disorders, such as, but not limited to asthma, include:glucocorticoids, such as, ciclesonide, beclomethasone, budesonide,flunisolide, fluticasone, mometasone, and triamcinolone; leukotrienemodifiers, such as, montelukast, zafirlukast, pranlukast, and zileuton;mast cell stabilizers, such as, cromoglicate (cromolyn), and nedocromil;antimuscarinics/anticholinergics, such as, ipratropium, oxitropium, andtiotropium; methylxanthines, such as, theophylline and aminophylline;antihistamine, such as, mepyramine (pyrilamine), antazoline,diphenhydramine, carbinoxamine, doxylamine, clemastine, dimenhydrinate,pheniramine, chlorphenamine (chlorpheniramine), dexchlorphenamine,brompheniramine, triprolidine, cyclizine, chlorcyclizine, hydroxyzine,meclizine, promethazine, alimemazine (trimeprazine), cyproheptadine,azatadine, ketotifen, acrivastine, astemizole, cetirizine, loratadine,mizolastine, terfenadine, fexofenadine, levocetirizine, desloratadine,fexofenadine; omalizumab, an IgE blocker; beta2-adrenergic receptoragonists, such as: short acting beta2-adrenergic receptor agonists, suchas, salbutamol (albuterol), levalbuterol, terbutaline, pirbuterol,procaterol, metaproterenol, fenoterol, bitolterol mesylate; andlong-acting beta2-adrenergic receptor agonists, such as, salmeterol,formoterol, bambuterol.

In one aspect, DP₂ anatogonists described herein are admistered incombination with one or more agents used to treat used to treat asthma,including, but not limited to: combination inhalers (fluticasone andsalmeterol oral inhalation (e.g. Advair)); inhaled Beta-2 agonists(albuterol inhaler; albuterol nebulizer solution; formoterol;isoproterenol oral inhalation; levalbuterol; metaproterenol inhalation;pirbuterol acetate oral inhalation; salmeterol aerosol inhalation;salmeterol powder inhalation; terbutaline inhaler); inhaledcorticosteroids (beclomethasone oral inhalation; budesonide inhalationsolution; budesonide inhaler; flunisolide oral inhalation; fluticasoneinhalation aerosol; fluticasone powder for oral inhalation; mometasoneinhalation powder; triamcinolone oral inhalation); leukotriene modifiers(montelukast; zafirlukast; pranlukast; tomelukast; zileuton); mast cellstabilizers (cromolyn inhaler; nedocromil oral inhalation); monoclonalantibodies (omalizumab); oral Beta-2 agonists (albuterol oral syrup;albuterol oral tablets; metaproterenol; terbutaline); bronchodilator(aminophylline; oxtriphylline; theophylline).

In one aspect, DP₂ anatogonists described herein are admistered incombination with one or more agents used to treat allergy, including,but not limited to: antihistamine and decongestant combinations(cetirizine and pseudoephedrine; desloratadine and pseudoephedrine ER;fexofenadine and pseudoephedrine; loratadine and pseudoephedrine);antihistamines (azelastine nasal spray; brompheniramine; brompheniramineoral suspension; carbinoxamine; cetirizine; chlorpheniramine;clemastine; desloratadine; dexchlorpheniramine ER; dexchlorpheniramineoral syrup; diphenhydramine oral; fexofenadine; loratadine;promethazine); decongestants (pseudoephedrine); leukotriene modifiers(montelukast; montelukast granules); nasal anticholinergics(ipratropium); nasal corticosteroids (beclomethasone nasal inhalation;budesonide nasal inhaler; flunisolide nasal inhalation; fluticasonenasal inhalation; mometasone nasal spray; triamcinolone nasalinhalation; triamcinolone nasal spray); nasal decongestants(phenylephrine); nasal mast cell stabilizers (cromolyn nasal spray).

In one aspect, DP₂ anatogonists described herein are admistered incombination with one or more agents used to treat chronic obstructivepulmonary disease (COPD), including, but not limited to:anticholinergics—ipratropium bromide oral inhalation); combinationInhalers (albuterol and ipratropium (e.g. Combivent, DuoNeb);fluticasone and salmeterol oral inhalation (e.g. Advair));corticosteroids (dexamethasone tablets; fludrocortisone acetate;hydrocortisone tablets; methylprednisolone; prednisolone liquid;prednisone oral; triamcinolone oral); inhaled Beta-2 Agonists (albuterolinhaler; albuterol nebulizer solution; formoterol; isoproterenol oralinhalation; levalbuterol; metaproterenol inhalation; pirbuterol acetateoral inhalation; salmeterol aerosol inhalation; salmeterol powderinhalation; terbutaline inhaler); inhaled Corticosteroids(beclomethasone oral inhalation; budesonide inhalation solution;budesonide inhaler; flunisolide oral inhalation; fluticasone inhalationaerosol; fluticasone powder for oral inhalation; triamcinolone oralinhalation); mukolytics (guaifenesin); oral Beta-2 agonists (albuteroloral syrup; albuterol oral tablets; metaproterenol; terbutaline);bronchodilator (aminophylline; oxtriphylline; theophylline).

In one embodiment, DP₂ anatogonists described herein are administered toa subject in combination with inhaled corticosteroids.

In one embodiment, DP₂ anatogonists described herein are administered toa subject in combination with beta2-adrenergic receptor agonists. In oneembodiment, DP₂ anatogonists described herein are administered to asubject in combination with short acting beta2-adrenergic receptoragonists. In one embodiment, DP₂ anatogonists described herein areadministered to a subject in combination with long-actingbeta2-adrenergic receptor agonists.

As discussed herein, the administration of compounds of any of Formula(I), Formula (II), or Formula (III) is designed to anatagonize theactivity of DP₂. For example, in specific embodiments, theadministration of a DP₂ inhibitor decreases signal transductioninitiated by PGD₂ within the individual

Thus, in accordance with one aspect, methods described herein includethe diagnosis or determination of whether or not a subject is sufferingfrom a PGD₂-dependent or PGD₂ mediated disease or condition byadministering to the subject a compound of any of Formula (I), Formula(II), or Formula (III) or pharmaceutical composition or medicament whichincludes a compound of any of Formula (I), Formula (II), or Formula(III) and determining whether or not the subject responds to thetreatment.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits cancomprise a carrier, package, or container that is compartmentalized toreceive one or more containers such as vials, tubes, and the like, eachof the container(s) comprising one of the separate elements to be usedin a method described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers are formed fromany acceptable material including, e.g., glass or plastic.

For example, the container(s) can comprise one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically comprise one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein.

Example 1 Synthesis of{3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-aceticacid (Compound 1-1)

Step 1: A solution of(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazole(Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989, 39, p 1519; 0.111g, 0.32 mmol) in DMF (5 mL) was treated with NaH (60% dispersion; ˜0.020g, ˜0.39 mmol) for 30 minutes at room temperature. Ethyl bromoacetate(71 μL, 0.65 mmol) was added and the mixture stirred overnight. Thesolution was poured into water, extracted with EtOAc (×2), washed withwater (×2) and brine (×2), dried over MgSO₄, and concentrated to give anoil (0.160 g). This oil was dissolved in THE (3 mL), MeOH (3 mL) and 1Naqueous NaOH (3 mL) and stirred overnight. Purification by reverse phasepreparative HPLC provided the title compound. [M+H]⁺=461.

Example 2 Synthesis of{(4-Fluoro-benzenesulfonyl)-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino}-aceticacid (Compound 1-2),3-{3-[(4-Fluoro-benzenesulfonyl)-(2-hydroxy-2-methyl-propyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionicacid (Compound 1-3), and4-FluoroN-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-(2-hydroxy-2-methyl-propyl)-benzenesulfonamide(Compound 1-4)

Step 1:

A solution of(3R)-3-(4-fluorophenylsulfonylamido)-1,2,3,4-tetrahydro-9-carbazolepropanoicacid sodium salt (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989,39, p 1519; 0.150 g, 0.34 mmol) in DMF (3 mL) was treated with NaH (60%dispersion; 0.016 g, 0.41 mmol) for 30 minutes at 0° C. Methylbromoacetate (35 μL, 0.38 mmol) was added and the mixture stirred for afurther 30 minutes. The solution was poured into water, extracted withEtOAc (×2), washed with water (×3), dried over MgSO₄, and concentrated.The residue was purified by column chromatography (silica gel) to give0.192 g of the O- and N-bis-alkylated product.

Step 2:

The bis-alkylated product (0.187 g, 0.33 mmol) in THF (3.6 mL) at 0° C.was treated with methyl magnesium iodide (3M in ether; 445 μL, 1.34mmol) and the reaction was allowed to warm to room temperature over 3hours. The mixture was quenched with saturated aqueous NH₄Cl andextracted with EtOAc (×2). The organic layer was dried over MgSO₄,concentrated and the residue dissolved in THF (5 mL) and 1N aqueous LiOH(5 mL) and stirred for 72 hours. The mixture was quenched with saturatedaqueous NH₄Cl and extracted with EtOAc (×2). Purification of the mixtureby reverse phase prep HPLC provided the title compounds. Massspectrometric data: Compound 1-2 [M+H]⁺=489; Compound 1-3 [M+H]⁺=489;Compound 1-4 [M+H]⁺=503.

Example 3 Synthesis of3-{3-[Carbamoylmethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionicacid (Compound 1-5)

Step 1.

A solution of(3R)-3-(4-fluorophenylsulfonylamido)-1,2,3,4-tetrahydro-9-carbazolepropanoicacid sodium salt (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989,39, p 1519; 0.150 g, 0.34 mmol) in DMF (3 mL) was treated with NaH (60%dispersion; 0.035 g, 0.41 mmol) for 30 minutes at 0° C. Bromoacetonitrile (26 μL, 0.38 mmol) was added and the mixture stirred for afurther 30 minutes. The solution was poured into water, extracted withEtOAc (×2), washed with water (×3), dried over MgSO₄, and concentrated.The residue was purified by column chromatography (silica gel) to give0.050 g of a mixture containing the O- and N-bis-alkylated product.

Step 2.

The bis-alkylated product (0.050 g) in MeOH (2 mL) at room temperaturewas treated with concentrated HCl (3 mL) and the reaction was heated to60° C. for 3 hours. The mixture was concentrated in vacuo, and theresidue was dissolved in THF (3 mL) and 1N aqueous LiOH (3 mL) andstirred for 16 hours. The mixture was quenched with 1N aqueous HCl (topH=3) and extracted with EtOAc (×3). Purification of the mixture byreverse phase preparative HPLC provided the title compound. [M+H]⁺=474.

Example 4 Synthesis of3-{3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionicacid (Compound 1-6)

Step 1:

A solution of(3R)-3-(4-fluorophenylsulfonylamido)-1,2,3,4-tetrahydro-9-carbazolepropanoicacid sodium salt (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989,39, p 1519; 0.150 g, 0.34 mmol) in DMF (3 mL) was treated with NaH (60%dispersion; 0.016 g, 0.41 mmol) for 30 minutes at 0° C. Methylbromoacetate (35 μL, 0.38 mmol) was added and the mixture stirred for afurther 30 minutes. The solution was poured into water, extracted withEtOAc (×2), washed with water (×3), dried over MgSO₄, and concentrated.The residue was purified by column chromatography (silica gel) to give0.192 g of the O- and N-bis-alkylated product.

Step 2:

The bis-alkylated product (0.34 mmol) in THF (2 mL) and 1N aqueous LiOH(2 mL) was stirred overnight. After acidification with 1N aqueous HCl(to pH˜3) the mixture was extracted with EtOAc (×3). Purification of themixture by reverse phase prep HPLC provided the title compound.[M+H]⁺=475.

Example 5a DP₂/CRTH2 Binding Assay

The ability of a compound to bind to the human DP₂ receptor is assessedvia a radioligand binding assay using [³H]PGD₂. HEK293 cells stablyexpressing recombinant human DP₂ are resuspended in 10 mM Hepes, 7.4containing 1 mM DTT, lysed and centrifuged at 75,000×g to pellet themembranes. The membranes are resuspended in 10 mM Hepes, 7.4 containing1 mM DTT and 10% glycerol to approximately 5 mg protein/ml. Membranes(2-10 μg protein/well) are incubated in 96-well plates with 1 nM[³H]PGD₂ and test compound in Assay Buffer (50 mM Hepes, 10 mM MnCl₂, 1mM EDTA, plus or minus 0.2% human serum albumin, pH 7.4) for 60 minutesat room temperature. The reactions are terminated by rapid filtrationthrough Whatman GF/C glass fibre filter plates. The filter plates werepre-soaked in 0.33% polythylenimine for 30 minutes at room temperaturethen washed in Wash Buffer (50 mM Hepes, 0.5 M NaCl pH 7.4) prior toharvesting. After harvesting, the filter plates are washed 3 times with1 ml cold Wash Buffer then dried. Scintillant is then added to theplates and the radioactivity retained on the filters is determined on aPackard TopCount (Perkin Elmer). Specific binding is determined as totalradioactive binding minus non-specific binding in the presence of 10 μMPGD₂. IC₅₀s were determined using GraphPad prism analysis of drugtitration curves. Compounds tested had an IC₅₀ of less than 100micromolar in this assay.

Example 5b GTPγS Binding Assay

The ability of a compound to inhibit binding of GTP to DP₂ is assessedvia a membrane GTPγS assay. CHO cells stably expressing the recombinanthuman CRTH2 receptor are resuspended in 10 mM Hepes, 7.4 containing 1 mMDTT, lysed and centrifuged at 75,000×g to pellet the membranes. Themembranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and10% glycerol. Membranes (˜12.5 μg per well) are incubated in 96-wellplates with 0.05 nM [³⁵S]-GTPγS, 80 nM PGD₂, 5 μM GDP, and test compoundin Assay Buffer (50 mM Hepes, pH 7.4, 100 mM NaCl, 5 mM MgCl₂ and 0.2%human serum albumin) for 60 minutes at 30° C. The reactions areterminated by rapid filtration through Whatman GF/B glass fibre filterplates. The filter plates are washed 3 times with 1 ml cold Assay Bufferand dried. Scintillant is then added to the plates and the radioactivityretained on the filters is determined on a Packard TopCount (PerkinElmer). Specific binding is determined as total radioactive bindingminus non-specific binding in the absence of the ligand (80 nM PGD₂).IC₅₀s were determined using Graphpad prism analysis of drug titrationcurves.

Example 5c Whole Blood Esoinophil Shape Change Assay

Blood is drawn from consenting human volunteers in EDTA vacutainer tubesand used within 1 hr of draw. A 98 μl aliquot of blood is mixed with 2μl of test compound (in 50% DMSO) in 1.2 ml polypropylene tubes. Theblood is vortexed and incubated at 37° C. for 15 minutes. 5 μl of 1 μMPGD₂ in PBS is added for a final concentration of 50 nM and the tubesbriefly vortexed. The reactions are incubated for exactly 5 minutes at37° C. and then terminated by placing the tubes on ice and immediatelyadding 250 μl of ice-cold 1:4 diluted Cytofix (BD Biosciences). Thereactions are transferred to 12×75 mM polystyrene round bottom tubes andthe red blood cells lysed by the addition of 3 ml ammonium chloridelysing solution (150 mM NH₄Cl, 10 mM KHCO₃, 0.1 mM EDTA disodium salt)and incubation at room temperature for 15 minutes. The cells arepelleted by spinning at 1300 rpm for 5 minutes at 4° C. and washed oncewith 3 ml ice-cold PBS. The cells are resuspended in 0.2 ml of ice-cold1:4 diluted Cytofix (BD Biosciences) and analyzed on a FACSCalibur (BDBiosciences) within 2 hours. Eosinophils were gated on the basis ofautofluorescence in the FL2 channel and shape change on 500 eosinophilswas assayed by forward scatter and side scatter analysis. The specificchange in shape induced by PGD₂ was calculated as the difference betweenthe percentage of high forward scatter eosinophils in the presence andabsence of PGD₂. IC₅₀s were determined using Graphpad Prism® analysis ofdrug titration curves.

Example 5d DP₁ Binding Assay

The ability of a compound to bind to the human DP1 receptor wasevaluated via a radioligand membrane binding assay using the DP₁selective synthetic ligand [³H]BWA868C. Packed human platelets(Biological Specialty Corporation), were resuspended in 6 volumes ofHepes/HBSS buffer (10 mM Hepes, 1 mM DTT in Hanks Balanced Salt Solution(HBSS), lysed and centrifuged at 75,000×g to pellet the membranes.Membranes were resuspended in Hepes/HBSS buffer to approximately 12 mgprotein/ml. Membranes (20 μg protein/well) are incubated in 96-wellplates with 2 nM [³H]BWA868C and test compound in Assay Buffer (50 mMHepes, 10 mM MnCl₂, 1 mM EDTA, plus or minus 0.2% human serum albumin,pH 7.4) for 60 minutes at room temperature. The reactions are terminatedby rapid filtration through Whatman GF/C glass fibre filter plates. Thefilter plates were pre-soaked in 0.33% polethylenimine for 30 minutes atroom temperature then washed in Wash Buffer (50 mM Hepes, 0.5 M NaCl pH7.4) prior to harvesting. After harvesting, the filter plates are washed3 times with 1 ml cold Wash Buffer then dried. Scintillant is then addedto the plates and the radioactivity retained on the filters isdetermined on a Packard TopCount (Perkin Elmer). Specific binding isdetermined as total radioactive binding minus non-specific binding inthe presence of 10 μM BW A868C. IC₅₀s were determined using GraphPadprism analysis of drug titration curves.

Example 6 Mouse Allergic Rhinitis Model

The compounds ability to inhibit allergen-induced sneezing and nasalrubbing is assessed using a mouse model of allergic rhinitis. Methodswere adapted from those detailed in Nakaya, M., et al. 2006, LaboratoryInvestigation, 86:917-926. Female BALB/c mice (20-25 g) are immunized byan intraperitoneal injection (i.p.) of 2 μg ovalbumin (OVA) complexedwith alum in a volume 0.2 ml on days 0 and 14. Seven days later (day 21)mice are challenged intranasally with 20 μl of a 10 mg/ml solution ofOVA. The challenge period occurs daily from days 21 to day 25. Mice(5-7/group) are randomly assigned to receive either compound or vehicleand are treated by oral gavage 1-2 hour prior to each OVA challenge. Thenumber of sneezes and nasal rubs are counted by an independent blindobserve during a period of 8 minutes immediately following OVA challengeon days 21, 23 and 25. A significant increase in allergen-inducedsneezing and nasal rubbing occurs over the 5-day challenge period.Inhibition of this effect by select compounds is determinedstatistically using Graphpad prism.

Example 7 Guinea Pig IV-DKPGD2-Induced Peripheral Blood Leukocyte Influx

The compounds ability to inhibit leukocyte migration in vivo wasassessed using intravenous injection of13,14-dihydro-15-keto-prostaglandin D2 (DK-PGD2). Methods were adaptedfrom those detailed Shichijo et al., 2003, Journal of Pharmacology andExperimental Therapeutics, 307:518-525. Male Hartley guinea pigs wereimmunized with ovalbumin (OVA) on day 0 by intraperitoneal (IP)injection of 1 ml of a 100 μg/ml solution in Imject Alum. They were thenused in the DK-PGD2 procedure between days 14 and 21. Subjects wererandomly assigned to receive either vehicle (0.5% methyl cellulose, 4ml/kg, oral (PO)) or one of three to four doses of test compound. Twohours or eighteen hours after dosing, animals were anesthetized withketamine and challenged with DK-PGD2 (1 mg/kg, IV). Thirty minutes afterIV administration, blood was collected via the marginal ear vein intoEDTA tubes for cell analysis. 10 μl blood was lysed in 190 μl waterfollowed by a further 20-fold dilution in PBS. A 10 μl fraction wasmixed with equal parts trypan blue and loaded on a hemocytometer. Cellswere visualized at a magnification of 40× using a LabPro lightmicroscope and totals counted and recorded. Cells are expressed as totalcells×10⁸ per ml of blood. Inhibition of this effect by select compoundsis determined statistically using Graphpad prism.

The compounds of Formula (I), Formula (II), or Formula (III) that weretested in Table 2 had IC₅₀ below 10 μM in the CRTH2 binding assay.

TABLE 2 Representative Biological Data Compound hDP2 μM hDP1 μM 1-1 A C1-2 C C 1-3 C C 1-4 C C 1-5 C C 1-6 C C Ramatroban B C A = less than 0.3μM; B = greater than 0.3 μM; C = greater than 1 μM.

Example 8 Clinical Trials in Humans

Study 1: Clinical Trial Evaluating Effect of Compound of Formula (I) onex vivo PGD2-Induced Blood Eosinophil Shape Change

In this double-blind, randomized, placebo-controlled, single ascendingdose study of Compound of Formula (I), (II), or (III) in healthyvolunteers the inhibition of ex vivo PGD2-induced blood eosinophil shapechange is determined to show proof of biochemical mechanism of DP2receptor antagonism. Eight subjects (6 active, 2 placebo) per dose levelare used. Pre dose blood is drawn and challenged with PGD2 to determinebaseline shape change as described above in Example 5. At varying timesafter dosing blood is drawn for both pharmacokinetic analyses of drugconcentration in blood, and also for PGD2 challenge and eosinophil shapechange determination. The extent of receptor blockage is determined fromthe relationship between drug blood concentration and percentageinhibition of eosinophil shape change.

Study 2: Clinical Trial Evaluating Effect of Compound of Formula (I),(II), or (III) on Allergen-Induced Nasal Symptoms and Inflammatory andAllergic Biomarkers

In this double-blind, randomized, placebo-controlled study of Compoundof Formula (I), (II), or (III) in individuals with allergic rhinitis theinhibition of nasal symptoms and allergic biomarkers is determinedfollowing nasal challenge with appropriate allergen. Fifteen subjects(10 active, 5 placebo) are used. Subjects are dosed for 7 days witheither placebo or an amount of compound of Formula (I), (II), or (III)that results in complete DP2 receptor block in an ex vivo PGD2-inducedblood eosinophil shape change pharmacodynamic study as described above.On day 7 subjects undergo nasal allergen challenge (2 hours post-dose)and early allergic response (0.25-1.0 hr) and late allergic response(4-24 hr) are evaluated as an increase from baseline for treated vsplacebo. In addition changes in inflammatory cell differentials, Th2cytokines and other inflammatory markers are determined as increase frombaseline for treated vs. placebo.

Compound of Formula (I), (II), or (III) Assay

The plasma concentrations of compound of Formula (I), (II), or (III) aredetermined by gas chromatography, giving a detection limit of 1 ng·ml-1(Ritter W. Determination of BAY u3405, a novel thromboxane antagonist,in plasma and urine by HPLC and GC. In: Reid E, Wilson I D, eds.Bioanalytical Approaches for Drugs, Including Anti-asthmatics andMetabolites. Methodological Surveys in Biochemistry and Analysis, 1992;22: 211-216).

Study 3—Vienna Challenge Chamber Study

Study design: The study is a randomised, double blind, placebocontrolled, two way crossover evaluation of compound of Formula (I),(II), or (III), given orally for eight days. There is a screening periodof one week and a washout period of three weeks between the twotreatment periods.

There is a follow up one week after the last dose of study drug. Thegroup of patients who receive the study drug for the first treatmentperiod and placebo for the second are designated group A, while thegroup of patients who receive placebo for the first treatment period andthe study drug for the second treatment period are designated group B.

Treatment plan and methods: The subjects undergo a complete screeningassessment to determine a baseline response to allergens. This screeningassessment takes place one week prior to the start of dosing.

Subjects commence dosing with compound of Formula (I), (II), or (III),or placebo on Day 1 of each treatment period of the study. Adverseevents, total nasal symptom score and concomitant medications are noted.

Subjects report back to the clinic on Day 2 of each treatment period fora 6 hour allergen challenge. The following measurements are obtained:

-   -   Total nasal symptom score (TNSS) (obstruction, rhinorrhoea,        itch, sneeze) with each symptom scored on a categorical scale        from 0 to 3 pre-challenge, every 15 mins from 0 to 6 h        post-start of challenge    -   Eye symptom score (watery eyes, itchy eyes, red eyes) with each        symptom scored on a categorical scale from 0 to 3 pre-challenge,        every 15mins from 0 to 6 h post-start of challenge    -   Other symptoms (cough, itchy throat, itchy ears) with each        symptom scored on a categorical scale from 0 to 3 pre-challenge        and every 15mins from 0 to 6 h post-start of challenge

Subjects report back to the clinic on Day 8 of each treatment period fora 6 hour allergen challenge and the measurements obtained on Day 2 arerepeated.

A final follow-up visit is conducted one after the last dose of testarticle in Treatment Period 2.

Pharmaceutical Compositions Example 9a Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of any of Formula (I), Formula (II), or Formula (III), isdissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. Themixture is incorporated into a dosage unit form suitable foradministration by injection.

Example 9b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of any of Formula (I), Formula (II), or Formula (III), is mixedwith 750 mg of starch. The mixture is incorporated into an oral dosageunit for, such as a hard gelatin capsule, which is suitable for oraladministration.

Example 9c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of any of Formula (I), Formula(II), or Formula (III), with 420 mg of powdered sugar mixed, with 1.6 mLof light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract.The mixture is gently blended and poured into a mold to form a lozengesuitable for buccal administration.

Example 9d Fast-Disintegrating Sublingual Tablet

A fast-disintegrating sublingual tablet is prepared by mixing 48.5% byweigh of a compound of Formula (I), Formula (II), or Formula (III),44.5% by weight of microcrystalline cellulose (KG-802), 5% by weight oflow-substituted hydroxypropyl cellulose (50 μm), and 2% by weight ofmagnesium stearate. Tablets are prepared by direct compression (AAPSPharmSciTech. 2006; 7(2):E41). The total weight of the compressedtablets is maintained at 150 mg. The formulation is prepared by mixingthe amount of compound of Formula (I) with the total quantity ofmicrocrystalline cellulose (MCC) and two-thirds of the quantity oflow-substituted hydroxypropyl cellulose (L-HPC) by using a threedimensional manual mixer (lnversina®, Bioengineering AG, Switzerland)for 4.5 minutes. All of the magnesium stearate (MS) and the remainingone-third of the quantity of L-HPC are added 30 seconds before the endof mixing.

Example 9e Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of any of Formula (I), Formula (II), or Formula (III), ismixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodiumchloride solution. The mixture is incorporated into an inhalationdelivery unit, such as a nebulizer, which is suitable for inhalationadministration.

Example 9f Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of any of Formula (I), Formula (II), or Formula (III), is mixedwith 2.5 g of methylcelluose (1500 mPa), 100 mg of methylparapen, 5 g ofglycerin and 100 mL of purified water. The resulting gel mixture is thenincorporated into rectal delivery units, such as syringes, which aresuitable for rectal administration.

Example 9g Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of any of Formula (I), Formula (II), or Formula (III), is mixedwith 1.75 g of hydroxypropyl celluose, 10 mL of propylene glycol, 10 mLof isopropyl myristate and 100 mL of purified alcohol USP. The resultinggel mixture is then incorporated into containers, such as tubes, whichare suitable for topicl administration.

Example 9h Ophthalmic Solution Composition

To prepare a pharmaceutical opthalmic solution composition, 100 mg of acompound of any of Formula (I), Formula (II), or Formula (III), is mixedwith 0.9 g of NaCl in 100 mL of purified water and filterd using a 0.2micron filter. The resulting isotonic solution is then incorporated intoophthalmic delivery units, such as eye drop containers, which aresuitable for ophthalmic administration.

Example 9i Nasal Spray Solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound ofany of Formula (I), Formula (II), or Formula (III), is mixed with 30 mLof a 0.05M phosphate buffer solution (pH 4.4). The solution is placed ina nasal administrator designed to deliver 100 μl of spray for eachapplication.

Example 9j Enema Solution

To prepare a pharmaceutical enema, mix 10 mL of 95% ethanol, 40 mL ofpropylene glycol, and 1.5 mL of benzyl alcohol; add 500 mg of any ofFormula (I), Formula (II), or Formula (III) and mix until dissolved. Add4.2 gm of HPMC and mix until well dispersed. Mix 0.1 gm of benzoic acidand 4.9 gm of sodium benzoate in about 40 mL of purified water. Mixtogether the two solutions, add an additional 60 mL of water and allowto thicken by standing.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A compound having the structure of Formula (II),or a pharmaceutically acceptable salt thereof:

wherein, R¹, R², R³, and R⁴ each are independently selected from H,halogen, —CN, —NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —S(═O)₂N(R¹³)₂,—NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³, —OCO₂R¹²—, —N(R¹³)₂,—C(═O)N(R¹³)₂, —OC(═O)N(R¹³)₂, —NHC(═O)R¹², —NHC(═O)OR¹², C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, anoptionally substituted cycloalkyl, an optionally substitutedheterocycloalkyl, optionally substituted phenyl, and an optionallysubstituted monocyclic heteroaryl; R⁵ is L⁵-X⁵; L⁵ is —C₁-C₆alkyl-,—C₁-C₆fluoroalkyl-, or —C₃-C₆cycloalkyl-, —C₁-C₆alkyl- (optionallysubstituted aryl)-, —C₁-C₆alkyl- (optionally substituted heteroaryl)-,an optionally substituted aryl, or an optionally substituted heteroaryl;X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH,—C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₇R¹²,—NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹²,—N(R¹³)₂, —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or—C(═NR¹⁴)N(R¹³)₂; R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl,an optionally substituted cycloalkyl, an optionally substitutedheterocycloalkyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, —C₁-C₆alkyl- (optionally substitutedcycloalkyl), —C₁-C₆alkyl- (optionally substituted heterocycloalkyl),—C₁-C₆alkyl- (optionally substituted aryl), or —C₁-C₆alkyl- (optionallysubstituted heteroaryl); R⁷ is L⁷-X⁷; L⁷ is C₁-C₆alkyl-,C₁-C₆fluoroalkyl, or an optionally substituted C₃-C₆cycloalkyl; X⁷ is—CO₇H, —CO₇R¹², —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH, —C(═O)NH—CN,tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₇R¹², —NHC(═O)R¹²,—NHC(═O)OR¹², —OH, —OR¹², —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂,—C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or—C(═NR¹⁴)N(R¹³)₂; R¹⁰ is H or C₁-C₄alkyl; R¹² is C₁-C₆alkyl,C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted benzyl or optionally substituted heteroaryl; eachR¹³ is independently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆fluoroalkyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocycloalkyl, an optionally substituted aryl, anoptionally substituted benzyl, and an optionally substituted heteroaryl;or two R¹³ groups attached to the same N atom are taken together withthe N atom to which they are attached to form an optionally substitutedheterocycloalkyl; R¹⁴ is selected from among H, —S(═O)₂R¹², —S(═O)₂NH₂,—C(═O)R¹², —CN, and —NO₂.
 2. A compound having the structure of Formula(III), or a pharmaceutically acceptable salt thereof:

wherein, R¹, R², R³, and R⁴ each are independently selected from H,halogen, —CN, —NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —S(═O)₂N(R¹³)₂,—NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³, —OCO₂R¹², —N(R¹³)₂,—C(═O)N(R¹³)₇, —OC(═O)N(R¹³)₂, —NHC(═O)R¹², —NHC(═O)OR¹², C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, anoptionally substituted cycloalkyl, an optionally substitutedheterocycloalkyl, optionally substituted phenyl, and an optionallysubstituted monocyclic heteroaryl; R⁵ is L⁵-X⁵; L⁵ is —C₁-C₆alkyl-,—C₁-C₆fluoroalkyl-, —C₃-C₆cycloalkyl-, —C₁-C₆alkyl- (optionallysubstituted aryl)-, —C₁-C₆alkyl- (optionally substituted heteroaryl)-,an optionally substituted aryl, or an optionally substituted heteroaryl;X⁵ is —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═)NH—OH,—C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹²,—NHC(═O)R¹², —NHC(═O)OR¹², —OH, —N(R¹³)₂, —C(═O)NHC(═O)R¹², or—SO₂NHC(═O)R¹²; R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, anoptionally substituted cycloalkyl, an optionally substitutedheterocycloalkyl, an optionally substituted aryl, or an optionallysubstituted heteroaryl; R⁷ is L⁷-X⁷; L⁷ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,or an optionally substituted C₃-C₆cycloalkyl; X⁷ is —CO₂H, —CO₂R¹²,—C(═O)N(R¹³)₂, tetrazolyl, —OH, or —C(═O)NHC(═O)R¹²; R¹⁰ is H orC₁-C₄alkyl; R¹² is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedbenzyl or optionally substituted heteroaryl; each R¹³ is independentlyselected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, anoptionally substituted cycloalkyl, an optionally substitutedheterocycloalkyl, an optionally substituted aryl, an optionallysubstituted benzyl, and an optionally substituted heteroaryl; two R¹³groups attached to the same N atom are taken together with the N atom towhich they are attached to form an optionally substitutedheterocycloalkyl.
 3. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein: R¹, R², R³, and R⁴ each areindependently selected from H, halogen, —CN, —OH, —OR¹³,—S(═O)₂C₁-C₆alkyl, —S(═O)₂N(R¹³)₂, —NHS(═O)₂R¹²,—OC(═O)R¹²—C(═O)N(R¹³)₂, —NHC(═O)R¹², C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄fluoroalkoxy, C₁-C₄alkoxy, and C₁-C₄heteroalkyl; L⁵ is C₁-C₆alkyl;X⁵ is —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —NHS(═O)₂R¹²,—S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, or —N(R¹³)₂; L⁷ isC₁-C₆alkyl; X⁷ is CO₂H, —CO₂(C₁-C₄alkyl), or —OH; R⁶ is an optionallysubstituted C₃-C₁₀ cycloalkyl, an optionally substitutedC₂-C₁₀heterocycloalkyl, an optionally substituted phenyl, an optionallysubstituted napthyl, an optionally substituted monocyclic heteroarylcontaining 0-3 N atoms; and R¹⁰ is H or —CH₃.
 4. The compound of claim3, or a pharmaceutically acceptable salt thereof, wherein: R¹, R², R³,and R⁴ each are independently selected from H, halogen, —CN, —OH,—S(═O)₂C₁-C₆alkyl, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy,C₁-C₄alkoxy, and C₁-C₄heteroalkyl; R⁶ is an optionally substitutedphenyl, an optionally substituted naphthyl, or an optionally substitutedmonocyclic heteroaryl containing 0-3 N atoms; and X⁵ is —CO₂R¹³, —CN,—C(═O)N(R¹³)₂, or —OH.
 5. The compound of claim 4, or a pharmaceuticallyacceptable salt thereof, wherein: R¹, R², R³, and R⁴ each areindependently selected from H, F, Cl, Br, I, —CN, —OH, —OCH₃,—S(═O)₂CH₃, —CH₃, and —CF₃; R¹⁰ is H.
 6. The compound of claim 5, or apharmaceutically acceptable salt thereof, wherein: R⁶ is an optionallysubstituted phenyl.
 7. A compound that is:{3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-aceticacid;{(4-Fluoro-benzenesulfonyl)-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino}-aceticacid;3-{3-[(4-Fluoro-benzenesulfonyl)-(2-hydroxy-2-methyl-propyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionicacid;4-FluoroN-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-(2-hydroxy-2-methyl-propyl)-benzenesulfonamide;3-{3-[Carbamoylmethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionicacid; or3-{3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionicacid; or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableinactive ingredient selected from pharmaceutically acceptable diluents,pharmaceutically acceptable excipients, and pharmaceutically acceptablecarriers.
 9. A method for treating PGD2-dependent or PGD2-mediateddisease or condition in a subject comprising administrating to thesubject a therapeutically effective amount of a compound of claim 2, ora pharmaceutically acceptable salt thereof, wherein the PGD₂-dependentor a PGD₂-mediated disease or condition is selected from asthma,rhinitis, allergic conjuctivitis, atopic dermatitis, chronic obstructivepulmonary disease (COPD), pulmonary hypertension, interstitial lungfibrosis, cystic fibrosis, arthritis, allergy, psoriasis, inflammatorybowel disease, adult respiratory distress syndrome, myocardialinfarction, aneurysm, stroke, cancer, wound healing, endotoxic shock,pain, inflammatory conditions, eosinophilic esophagitis,eosinophil-associated gastrointestinal disorders (EGID), idiopathichypereosinophilic syndrome, otitis, airway constriction, mucussecretion, nasal congestion, increased microvascular permeability andrecruitment of eosinophils, urticaria, sinusitis, angioedema,anaphylaxia, chronic cough and Churg Strauss syndrome.
 10. Apharmaceutical composition comprising a compound of claim 2, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable inactive ingredient selected frompharmaceutically acceptable diluents, pharmaceutically acceptableexcipients, and pharmaceutically acceptable carriers.
 11. Apharmaceutical composition comprising a compound of claim 7, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable inactive ingredient selected frompharmaceutically acceptable diluents, pharmaceutically acceptableexcipients, and pharmaceutically acceptable carriers.